[(alkoxy)pyridinyl]amine compounds which are useful in the treatment of gastrointestinal disorders

ABSTRACT

The present invention relates to N-pyridylamidine and N-pyridylguanidine derivatives of general formula (I) in which: Ar 1  is an optionally substituted phenyl ring; Ar 2  is an optionally substituted phenyl ring; R 1  is hydrogen or C 1-4  alkyl; R 2  is hydrogen or C 1-4  alkyl; R 3  is hydrogen or C 1-4  alkyl; R 4  is hydrogen, halogen, C 1-6  alkyl or C 1-6  alkoxy; X is CH 2  or NR 5 , and R 5  is hydrogen or C 1-4  alkyl, and the salts thereof, and their use in therapy as gastric acid secretion inhibitors.

This application is a 371 of PCT/EP93/00174 filed Jan. 26, 1993.

The present invention relates to novel substituted amidine derivatives,processes for their preparation, pharmaceutical compositions containingthem, and their use in therapy, in particular as gastric acid secretioninhibitors.

The present invention, therefore, provides compounds of structure (I):##STR1## in which: Ar¹ is an optionally substituted phenyl ring;

Ar² is an optionally substituted phenyl ring;

R¹ is hydrogen or C₁₋₄ alkyl;

R² is hydrogen or C₁₋₄ alkyl;

R³ is hydrogen or C₁₋₄ alkyl;

R⁴ is hydrogen, halogen, C₁₋₆ alkyl or C₁₋₆ alkoxy,

X is CH₂ or NR⁵, and

R⁵ is hydrogen or C₁₋₄ alkyl, and the salts thereof.

Suitably, Ar¹ is an optionally substituted phenyl ring.

Suitable substituents for the phenyl ring Ar¹ include, for example, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, halogen, nitro, cyano, amino,hydroxy, carbamoyl, carboxy, C₁₋₆ alkanoyl, trifluoromethyl and C₁₋₄alkylenedioxy substituents such as methylenedioxy (--OCH₂ O--). Thephenyl rings may be substituted by a single substituent, or up to fivesubstituents as may be synthetically accessible (for example,2,3,4,5,6-pentafluorophenyl). Preferably, the group Ar¹ is unsubstitutedphenyl, or phenyl substituted by 1 or more substituents selected fromC₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, halogen, cyano, amino, hydroxy,carbamoyl, carboxy, C₁₋₆ alkanoyl, trifluoromethyl or by a singlesubstituent in association with a C₁₋₄ alkylenedioxy. The phenyl ringmay be substituted by a single substituent or up to 5 substituents asmay be synthetically accessible (for example,2,3,4,5,6-pentafluorophenyl). More preferably, Ar¹ is unsubstitutedphenyl, or phenyl substituted by one or two substituents selected fromC₁₋₆ alkyl, C₁₋₆ alkoxy and halogen. Most preferably Ar¹ isunsubstituted phenyl or a phenyl group substituted by a single C₁₋₆alkyl or halogen (in particular in the 2-position of the ring), orphenyl substituted by 2 halogen atoms (in particular 2 chlorine orfluorine atoms in the 2- and 6-positions of the ring or a chlorine atomin the 2-position and a fluorine atom in the 6-position of the ring).

Suitably R¹ is hydrogen or C₁₋₄ alkyl; preferably R¹ is hydrogen.

Suitably, R² is hydrogen or C₁₋₄ alkyl; preferably R² is hydrogen.

Suitably, R³ is hydrogen or C₁₋₄ alkyl; preferably R³ is hydrogen.

Suitably, R⁴ is hydrogen, halogen, C₁₋₆ alkyl or C₁₋₆ alkoxy; preferablyR⁴ is hydrogen.

Suitably, Ar² is an optionally substituted phenyl ring.

Suitable substituents for the phenyl ring Ar² include, for example, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, halogen, nitro, cyano, amino,hydroxy, carbamoyl, carboxy, C₁₋₆ alkanoyl, trifluoromethyl and C₁₋₄alkylenedioxy substituents such as methylenedioxy (--OCH₂ O--). Thephenyl rings may be substituted by a single substituent, or up to fivesubstituents as may be synthetically accessible.

Preferably, Ar² is unsubstituted phenyl or phenyl substituted by asingle substituent selected from C₁₋₄ alkyl, C₁₋₄ alkoxy or halogen.More preferably, Ar² is unsubstituted phenyl or phenyl substituted by asingle halogen atom, in particular chlorine in the 4-position of thering.

The compounds of the present invention can be prepared by processesanalogous to those known to those skilled in the art. In a furtheraspect, there is, therefore provided a process for preparing compoundsof structure (I) and salts thereof, which comprises (a) for compounds inwhich X is CH₂, reaction of a compound of structure (II): ##STR2## inwhich Ar¹, R¹, R³ and R⁴ are as described for structure (I) with acompound of structure (HI) in which Ar² is as described for structure(I) and Y is a leaving group; (b) for compounds in which X is NR⁵ and R⁵is hydrogen, reaction of a compound of structure (IV) ##STR3## in whichAr¹, Ar² and R¹, R³ and R⁴ are as described for structure (I) and Y¹ isa leaving group with an amine of structure H₂ NR² in which R² is asdescribed for structure (I); (c) for compounds in which X is NR⁵

(i) reaction of a compound of structure (II) with a compound ofstructure (V) ##STR4## in which Y² is a leaving group and Ar², R² and R⁵are as described for structure (I); or

(ii) reaction of a compound of structure (VI) ##STR5## in which R¹ to R⁴and Ar¹ are as described for structure (I) and Y² is a leaving group,with a compound of structure HNR⁵ Ar² (VII) in which R⁵ and Ar² are asdescribed for structure (I), and optionally thereafter, forming a salt.

Suitable leaving groups Y include for example halide, or R⁶ O in whichR⁶ is C₁₋₄ alkyl. Preferably Y is R⁶ O.

Suitable leaving groups Y¹ include for example SH activated by mercuryas described in the specific examples herein.

Suitable leaving groups Y² include for example OR⁷, SR⁷, halogen orsulphonic acid, in which R⁷ is C₁₋₄ alkyl; preferred groups Y² includeSCH₃.

The reaction between compounds of structure (II) and compounds ofstructure (III) can be carried out in a suitable solvent at atemperature of between ambient and the reflux temperature of the solventused, for as long as it takes for complete reaction to occur. Suitablesolvents include, for example, C₁₋₄ alkanols such as ethanol ormethanol. Preferably, the reaction can be carried out in ethanol as asolvent, at reflux temperature.

The reaction between compounds of structure (IV) with an amine H₂ NR²can be carried out in the presence of a suitable solvent such as a C₁₋₄alkanol, in particular methanol, at ambient temperature or elevatedtemperature, until reaction is complete.

The reaction between compounds of structure (II) and (V) can be carriedout in the presence of a suitable solvent such as a C₁₋₄ alkanol such asmethanol or ethanol.

The reaction between a compound of structure (VI) and an amine ofstructure (VII) can be carried out in the presence of a suitable solventsuch as a C₁₋₄ alkanol such as methanol or ethanol.

The intermediate compounds of structures (II) and (III) can be preparedfrom commercially available starting materials, using standardtechniques practised in the art of organic chemistry. For example,compounds of structure (II) can be prepared by reaction of 2-amino-3-hydroxypyridine with the appropriate compound Ar¹ CHR¹ X, in which Ar¹and R¹ are as described for structure (I) and X is halogen, inparticular bromine, in a suitable solvent, in the presence of a base ashereinafter described. Compounds of structure (III), for example, inwhich Y is ethoxy, can be prepared by reaction of the appropriate cyanoderivative Ar² CH₂ CN, in which Ar² is as described for structure (I),with dry hydrogen chloride gas in ethanol as a reaction solvent.

The compounds of structure (I) and their pharmaceutically acceptablesalts exert an anti-secretory effect by inhibition of thegastrointestinal H⁺ K⁺ ATPase enzyme (Fellenius, E., Berglindh, T.,Sachs, G., Olke, L., Elander, B., Sjostrand, S. E., and Wallmark, B.,1981, Nature, 290, 159-61).

In a further aspect therefore the present invention provides compoundsof structure (I) and pharmaceutically acceptable salts thereof for usein therapy. The compounds of structure (I) and their pharmaceuticallyacceptable salts inhibit exogenously and endogenously stimulated gastricacid secretion and are useful in the treatment of gastrointestinaldiseases in mammals, in particular humans.

Such diseases include, for example, gastric and duodenal ulcers,aspiration pneumonitis and Zollinger-Ellison Syndrome.

Further, the compounds of structure (I) can be used in the treatment ofother disorders where an anti-secretory effect is desirable for examplein patients with gastritis, NSAID induced gastritis, acute .upperintestinal bleeding, in patients with a history of chronic and excessivealcohol consumption, and in patients with gastro oesophageal refluxdisease (GERD).

In therapeutic use, the compounds of the present invention are usuallyadministered in a standard pharmaceutical composition. The presentinvention therefore provides in a further aspect pharmaceuticalcompositions comprising a compound of structure (l) or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.

The compounds of structure (I) and their pharmaceutically acceptablesalts which are active when given orally can be formulated as liquids,for example syrups, suspensions or emulsions, tablets, capsules andlozenges.

A liquid formulation will generally consist of a suspension or solutionof the compound or pharmaceutically acceptable salt in a suitable liquidcarrier(s) for example, ethanol, glycerine, non-aqueous solvent, forexample polyethylene glycol, oils, or water with a suspending agent,preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routineencapsulation procedures. For example, pellets containing the activeingredient can be prepared using standard carriers and then filled intoa hard gelatin capsule; alternatively, a dispersion or suspension can beprepared using any suitable pharmaceutical carrier(s), for exampleaqueous gums, celluloses, silicates or oils and the dispersion orsuspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension ofthe compound or pharmaceutically acceptable salt in a sterile aqueouscarrier or parenterally acceptable oil, for example polyethylene glycol,polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.Alternatively, the solution can be lyophilised and then reconstitutedwith a suitable solvent just prior to administration.

A typical suppository formulation comprises a compound of formula (I) ora pharmaceutically acceptable salt thereof which is active whenadministered in this way, with a binding and/or lubricating agent suchas polymeric glycols, gelatins or cocoa butter or other low meltingvegetable or synthetic waxes or fats.

Preferably the composition is in unit dose form such as a tablet orcapsule.

Each dosage unit for oral administration contains suitably from 1 to1000 mg, preferably from 1 to 500 mg (and for parenteral administrationcontains preferably from 0.1 to 25 rag) of a compound of the formula (I)or a pharmaceutically acceptable salt thereof calculated as the freebase.

The present invention also provides a method of inhibiting gastric acidsecretion which comprises administering to a mammal in need thereof aneffective amount of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof; and a method of treatment of diseases of thestomach or intestine based on increased acid secretion which comprisesadministering to a mammal in need thereof an effective amount of acompound of the formula (I) or a pharmaceutically acceptable saltthereof.

The pharmaceutically acceptable compounds of the invention will normallybe administered to a subject for the treatment of gastrointestinaldiseases and other conditions caused or exacerbated by gastric acidity.The daily dosage regimen for an adult patient may be, for example, anoral dose of between 1 mg and 1000 mg, preferably between 1 mg and 500mg, or an intravenous, subcutaneous, or intramuscular dose of between0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compoundof the formula (I) or a pharmaceutically acceptable salt thereofcalculated as the free base, the compound being administered 1 to 4times per day.

Suitably the compounds will be administered for a period of continuoustherapy, for example for a week or more.

In addition, the compounds of the present invention can beco-administered with further active ingredients, such as antacids (forexample magnesium carbonate or hydroxide and aluminium hydroxide),non-steroidal anti-inflammatory drugs (for example indomethacin, aspirinor naproxen), steroids, or nitrite scavengers (for example ascorbic acidor aminosulphonic acid), or other drugs used for treating gastric ulcers(for example histamine H₂ -antagonists such as cimetidine) or agentshaving activity against Helicobacter pylori organisms, for exampleantibiotics such as amoxicillin.

The following examples illustrate the invention. Temperatures arerecorded in degrees centigrade.

EXAMPLE 1 N-(3-(Benzyloxy)-2-pyridyl)phenylacetamidine

A mixture of 2-amino-3-benzyloxypyridine (2.5 g, 12.5 mmol) and ethylphenylacetimidate hydrochloride (2.5 g, 12.5 mmol) in ethanol (100 ml)was heated under reflux for 1 hour. The solvent was evaporated in vacuo,and the residue taken up in chloroform, washed with aqueous sodiumbicarbonate, dried and the chloroform evaporated. Treatment withcharcoal and recrystallisation from ethyl acetate/petroleum ether gavethe product (0.62 g), m.p. 114°-116° C.

C₂₀ H₁₉ N₃ O

Found C 75.78, H 6.04, N 13.21

Requires C 75.69, H 6.03, N 13.24

EXAMPLE 2 N-(3-(Benzyloxy)-2-pyridyl)-2-methylphenylacetamidinehydrochloride (a) Ethyl 2-methylphenylacetimidate hydrochloride

A solution of 2-methylbenzyl cyanide (25 g, 0.19 mol) in absoluteethanol (100 ml) was treated with dry HCI gas with ice cooling for 1hour. The solvent was evaporated in vacuo, and the residual oiltriturated with ether. The solid was filtered off, washed with ether anddried (32.1 g, 95%), then used in subsequent steps without furtherpurification.

(b) N-(3-(Benzyloxy)-2-pyridyl)-2-methylphenylacetamidine hydrochloride

A mixture of 2-amino-3-benzyloxypyridine (4.0 g, 20 mmol) and ethyl2-methylphenylacetimidate hydrochloride (4.69 g, 22 mmol) in ethanol (80ml) was heated under reflux for 1 hour. Evaporation of the solvent gavean oil which was purified by flash chromatography (chloroform/methanol10:1). The product was obtained as a white crystalline solid (1.2 g),m.p. 119°-120° C.

C₂₁ H₂₁ N₃ O.HCl.0.2H₂ O

Found C 67.60, H 6.04, N 11.41

Requires C 67.89, H 6.07, N 11.31

EXAMPLE 3 N-(3-(Benzyloxy)-2-pyridyl)-4-methoxyphenylacetamidinehydrochloride (a) Ethyl 4-methoxyphenylacetimidate hydrochloride

A solution of 4-methoxyphenylacetonitrile (50 g, 0.34 mol) in absoluteethanol (200 ml) was treated with dry HCl gas with ice cooling for 1hour. The solvent was evaporated in vacuo, and the residual oiltriturated with ether. The solid was filtered off, washed with ether anddried (66 g, 84%), then used in subsequent steps without furtherpurification.

(b) N-(3-(Benzyloxy)-2-pyridyl)-4-methoxyphenylacetamidine hydrochloride

A mixture of 2-amino-3-benzyloxypyridine (4.0 g, 20 mmol) and ethyl4-methoxyphenylacetimidate hydrochloride (5.04 g, 22 mmol) in ethanol(80 ml) was heated under reflux for 2 hours. Evaporation of the solventgave an oil which was purified by flash chromatography(chloroform/methanol) to give the product (1.27 g), m.p. 75°-78° C.

C₂₁ H₂₁ N₃ O₂.HCl.0.5H₂ O

Found C 64.39, H 5.68, N 10.78

Requires C 64.19, H 5.90, N 10.69

EXAMPLE 4 N-(3-(Benzyloxy)-2-pyridyl)-4-fluorophenylacetamidine (a)Ethyl 4-fluorophenylacetimidate hydrochloride

A solution of 4-fluorophenylacetonitrile (50 g, 0.37 mol) in absoluteethanol (300 ml) was treated with dry HCl gas with ice cooling for 1hour. The solvent was evaporated in vacuo, and the residual oiltriturated with ether. The solid was filtered off, washed with ether anddried (67 g, 83%), then used in subsequent steps without furtherpurification.

(b) N-(3-(Benzyloxy)-2-pyridyl)-4-fluorophenylacetamidine

A mixture of 2-amino-3-benzyloxypyridine (4.84 g, 24.2 mmol) and ethyl4-fluorophenylacetimidate hydrochloride (5.8 g, 26.7 mmol) in ethanol(80 ml) was heated under reflux for 2 hours. Evaporation of the solventgave an oil which was converted to the free base and purified by flashchromatography (chloroform/methanol) to obtain the product (0.49 g),m.p. 86°-93° C.

C₂₀ H₁₈ FN₃ O.0.5H₂ O

Found C 69.72, H 5.32, N 12.31, F 55.47

Requires C 69.75, H 5.56, N 12.20, F 55.51

EXAMPLE 5 N-(3-(2-Methylenedioxy)-2-pyridyl)phenylacetamidinehydrochloride (a) 2-Amino-3-(2-methylbenzyloxy)pyridine

A mixture of a -bromo-o-xylene (89.6 g, 0.48 mol) and2-amino-3-hydroxypyridine (48 g, 0.436 mol) in 40% aqueous sodiumhydroxide solution (250 ml) and dichloromethane (250 ml) was treatedwith Adogen 464 (5 ml) and stirred vigorously at room temperature for 16hours. The aqueous layer was extracted with dichloromethane and thecombined organic layers washed with water, dried and evaporated.Chromatography (silica gel, chloroform) gave the product as an oil whichlater solidified (45.4 g, 49%), m.p. 96°-98° C.

(b) N-(3-(2-Methylbenzyloxy)-2-pyridyl)phenylacetamidine hydrochloride

A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (5.2 g, 24.2 mmol)and ethyl phenylacetimidate hydrochloride (5.32 g, 26.7 mmol) in ethanol(80 ml) was heated under reflux for 2 hours. Evaporation of the solventgave an oil which was taken up in chloroform, filtered to remove aninsoluble white solid, and purified by flash chromatography(chloroform/methanol) to obtain the product (0.85 g), m.p. 175°-178° C.

C₂₁ H₂₁ N₃ O.HCl.0.1H₂ O

Found C 67.98, H 6.09, N 11.31

Requires C 68.22, H 6.05, N 11.36

EXAMPLE 6 N-(3-(2-Methylbenzyloxy)-2-pyridyl)-2-methylphenylacetamidinehydrochloride

A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (5.2 g, 24.2 mmol)and ethyl 2-methylphenylacetimidate hydrochloride (5.7 g, 26.7 mmol) inethanol (80 ml) was heated under reflux for 2 hours. Evaporation of thesolvent gave an oil which was purified by flash chromatography(chloroform/methanol) to obtain the product (1.37 g), m.p. 147°-154° C.

C₂₂ H₂₃ ^(N) ₃ O.HCl.0.5H₂ O

Found C 67.61, H 6.39, N 10.74

Requires C 67.59, H 6.45, N 10.74

EXAMPLE 7 N-(3-(2-Methylbenzyloxy)-2-pyridyl)-4-methoxyphenylacetamidinehydrochloride

A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (5.2 g, 24.2 mmol)and ethyl 4-methoxyphenylacetimidate hydrochloride (6.1 g, 26.7 mmol) inethanol (80 ml) was heated under reflux for 2 hours, then the solventevaporated. The residue was taken up in chloroform, filtered to removean insoluble solid, and the filtrate purified by flash chromatography(chloroform/methanol) to obtain the product (0.29 g), m.p. 58°-67° C.

C₂₂ H₂₃ N₃ O₂.HCl.0.7H₂ O

Found C 64.36, H 5.98, N 10.19

Requires C 64.36, H 6.23, N 10.23

EXAMPLE8 N-(3-(2-Methylbenzyloxy)-2-pyridyl)-4-fluorophenylacetamidinehydrochloride

A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (5.2 g, 24.2 mmol)and ethyl 4-fluorophenylacetimidate hydrochloride (5.8 g, 26.7 mmol) inethanol (80 ml) was heated under reflux for 2 hours, then the solventevaporated. The residue was purified by flash chromatography(chloroform/methanol) to obtain the product as a foam (0.49 g), m.p.59°-64° C.

C₂₁ H₂₀ FN₃ O.HCl

Found C 65.32, H 5.46, N 10.99, F 5.36

Requires C 65.37, H 5.49, N 10.89, F 4.92

EXAMPLE 9 N-(3-(4-fluorobenzyloxy)-2-pyridyl)phenylacetamidinehydrochloride (a) 2-Amino-3-(4-fluorobenzyloxy)pyridine

A mixture of 4-fluorobenzyl bromide (75 g, 0.396 mol) and2-amino-3-hydroxypyridine (39.6 g, 0.36 mol) in 40% aqueous sodiumhydroxide solution (250 ml) and dichloromethane (250 ml) was treatedwith Adogen 464 (5 ml) and stirred vigorously at room temperature for 16hours. The aqueous layer was extracted with dichloromethane and thecombined organic layers washed with water, dried and evaporated.Chromatography (silica gel, chloroform) gave the product as an oil whichlater solidified (45.4 g, 49%), m.p. 96°-98° C.

(b) N-(3-(4-Fluorobenzyloxy)-2-pyridyl)phenylacetamidine hydrochloride

A mixture of 2-amino-3-(4-fluorobenzyloxy)pyridine (5.42 g, 24.2 mmol)and ethyl phenylacetimidate hydrochloride (6.28 g, 26.7 mmol) in ethanol(80 ml) was heated under reflux for 2 hours. Evaporation of the solventgave an oil which was taken up in chloroform, filtered to remove aninsoluble white solid, and purified by flash chromatography(chloroform/methanol) to obtain the product (0.85 g), m.p. 175°-178° C.

C₂₀ H₁₈ FN₃ O.HCl

Found C 64.12, H 5.24, N 10.87

Requires C 64.60, H 5.15, N 11.30

EXAMPLE 10 N-(3-(4-Fluorobenzyloxy)-2-pyridyl)-2-methylphenylacetamidinehydrochloride

A mixture of 2-amino-3-(4-fluorobenzyloxy)pyridine (4.36 g, 20 mmol) andethyl 2methylphenylacetimidate hydrochloride (4.69 g, 22 mmol) inethanol (80 ml) was heated under reflux for 2 hours. Evaporation of thesolvent gave an oil, which was purified by flash chromatography(chloroform/methanol) to obtain the product (1.2 g), m.p. 199°-200° C.

C₂₁ H₂₀ FN₃ O.HCl

Found C 65.06, H 5.36, N 10.94

Requires C 65.36, H 5.48, N 10.89

EXAMPLE 11N-(3-(4-Fluorobenzyloxy)-2-pyridyl)-4-methoxyphenylacetamidinehydrochloride

A mixture of 2-amino-3-(4-fluorobenzyloxy)pyridine (4.36 g, 20 mmol) andethyl 4-methoxyphenylacetimidate hydrochloride (5.04 g, 22 mmol) inethanol (80 ml) was heated under reflux for 2 hours. Evaporation of thesolvent gave an oil, which was purified by flash chromatography(chloroform/methanol) to obtain the product as a hygroscopic gum (1.2g), m.p. 199°-200° C.

C₂₁ H₂₀ FN₃ O₂.HCl.0.4H₂ O

Found C 61.61, H 5.20, N 10.35, F 4.16

Requires C 61.65, H 5.37, N 10.29, F 4.64

EXAMPLE 12 N-(3-(4-Methoxybenzyloxy)-2-pyridyl)phenylacetamidinehydrochloride (a) 2- Amino- 3-(4-methoxybenzyloxy)pyridine

A mixture of 4-methoxybenzyl bromide (25 g, 0.159 mol) and2-amino-3-hydroxypyridine (15.9 g, 0.145 mol) in 40% aqueous sodiumhydroxide solution (150 ml) and dichloromethane (150 ml) was treatedwith Adogen 464 (5 ml) and stirred vigorously at room temperature for 16hours. The mixture was diluted with further water and dichloromethane,the product extracted into dichloromethane, and the combined organiclayers washed with water, dried and evaporated. The resulting solid waswashed with ether to yield the product (25.6 g, 70%)

(b) N-(3-(4-Methoxybenzyloxy)-2-pyridyl)phenylacetamidine hydrochloride

A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (4.6 g, 20 mmol) andethyl phenylacetimidate hydrochloride (4.39 g, 26 mmol) in ethanol (80ml) was heated under reflux for 2 hours. Evaporation of the solvent gavean oil which was purified by flash chromatography (chloroform/methanol)to obtain the product (0.75 g), m.p. 188°-192° C.

C₂₁ H₂₁ N₃ O₂.HCl

Found C 65.72, H 5.78, N 10.89, Cl 9.11

Requires C 65.71, H 5.78, N 10.95, Cl 9.24

EXAMPLE 13N-(3-(4-Methoxybenzyloxy)-2-pyridyl)-2-methylphenylacetamidine

A mixture of 2-amino-3-(4-methoxybenzyloxy)pyridine (4.6 g, 20 mmol) andethyl 2methylphenylacetimidate hydrochloride (4.69 g, 22 mmol) inethanol (80 ml) was heated under reflux for 2 hours. Evaporation of thesolvent gave an oil which was taken up in chloroform, convened to thefree base by washing with aqueous sodium bicarbonate, and purified byflash chromatography (chloroform/methanol) to obtain the product as agum (0.38 g).

C₂₂ H₂₃ N₃ O₂.0.8H₂ O

Found C 70.14, H 6.28, N 11.20

Requires C 70.30, H 6.79, N 11.18

EXAMPLE 14 N-(3-(2,4,6-Trimethylbenzyloxy)-2-pyridyl)phenylacetamidinehydrochloride (a) 2-Amino-3-(2,4,6-trimethylbenzyloxy)pyridine

A mixture of 2,4,6-trimethylbenzyl chloride (50 g, 0.296 mol) and2-amino-3hydroxypyridine (29.6 g, 0.269 mol) in 40% aqueous sodiumhydroxide solution (200 ml) and dichloromethane (200 ml) was treatedwith Adogen 464 (5 ml) and stirred vigorously at room temperature for 16hours. The product was extracted into dichloromethane and purified byflash chromatography (silica, chloroform) to yield a solid (10.1 g,14%), m.p. 160°-166° C.

(b) N-(3-(2,4,6-Trimethylbenzyloxy)-2-pyridyl)phenyl-acetamidinehydrochloride

A mixture of 2-amino-3-(2,4,6-trimethylbenzyloxy)pyridine (4.84 g, 20mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) inethanol (80 ml) was heated under reflux for 2 hours. Evaporation of thesolvent gave an oil which was purified by flash chromatography(chloroform/methanol) to obtain the product (1.95 g), m.p. 173°-178° C.

C₂₃ H₂₅ N₃ O.HCl.0.5H₂ O

Found C 68.59, H 6.47, N 10.44, Cl 8.41

Requires C 68.21, H 6.72, N 10.37, Cl 8.75

EXAMPLE 15 N-(3-(2,6-Dichiorobenzyloxy)-2-pyridyl)phenylacetamidinehydrochloride (a) 2-Amino-3-(2,6-dichlorobenzyloxy)pyridine

A mixture of 2,6-dichlorobenzyl bromide (50 g, 0.209 mol) and2-amino-3hydroxypyridine (20.9 g, 0.19 mol) in 40% aqueous sodiumhydroxide solution (200 ml) and dichloromethane (200 ml) was treatedwith Adogen 464 (5 ml) and stirred vigorously at room temperature for 16hours. A further 200 ml of water was added and the product extractedinto dichloromethane, dried, and the solvent evaporated to yield a solid(43.1 g, 76%), m.p. 141°-142° C.

(b) N-(3-(2,6-Dichlorobenzyloxy)-2-pyridyl)phenyl-acetamidinehydrochloride

A mixture of 2-amino-3-(2,6-dichlorobenzyloxy)pyridine (5.38 g, 20 mmol)and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol(80 ml) was heated under reflux for 2 hours. Evaporation of the solventgave an oil which was purified by flash chromatography(chloroform/methanol) to obtain the product as a hygroscopic foam (1.52g), m.p. 69°-74° C.

C₂₀ H₁₇ Cl₂ N₃ O.1.1HCl.0.2H₂ O

Found C 55.73, H 4.32, N 9.75, Cl 25.50

Requires C 55.44, H 4.14, N 9.58, Cl 25.76

EXAMPLE 16 N-(3-(2,6-Difluorobenzyloxy)-2-pyridyl)Phenylacetamidinehydrochloride (a) 2-Amino-3-(2,6-difluorobenzyloxy)pyridine

A mixture of 2,6-difluorobenzyl bromide (25 g, 0.121 mol) and2-amino-3hydroxypyridine (12.1 g, 0.11 mol) in 40% aqueous sodiumhydroxide solution (200 ml) and dichloromethane (200 ml) was treatedwith Adogen 464 (5 ml) and stirred vigorously at room temperature for 16hours. A further 200 ml of water was added and the product extractedinto dichloromethane, dried, and the solvent evaporated to yield a solid(18.5 g, 65%), m.p. 124°-128° C.

(b) N-(3-(2,6-Difluorobenzyloxy)-2-pyridyl)phenyl-acetamidinehydrochloride

A mixture of 2-amino-3-(2,6-difluorobenzyloxy)pyridine (4.72 g, 20 mmol)and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol(80 ml) was heated under reflux for 2 hours. Evaporation of the solventgave an oil which was purified by flash chromatography(chloroform/methanol) to obtain the product as a hygroscopic glass (0.43g), m.p. 45°-50° C.

C₂₀ H₁₇ F₂ N₃ O.0.8HCl.0.8H₂ O

Found C 60.72, H 4.67, N 10.85, Cl 7.24

Requires C 60.51, H 4.92, N 10.58, Cl 7.15

EXAMPLE 17N-(3-(2,6-Difluorobenzyloxy)-2-pyridyl)-2-methylphenylacetamidinehydrochloride

A mixture of 2-amino-3-(2,6-difluorobenzyloxy)pyridine (4.72 g, 20 mmol)and ethyl 2methylphenylacetimidate hydrochloride (4.69 g, 22 mmol) inethanol (80 ml) was heated under reflux for 2 hours. Evaporation of thesolvent gave art oil which was purified by flash chromatography(chloroform/methanol) to obtain the product (0.18 g), m.p. 127°-135° C.

C₂₁ H₂₀ F₂ N₃ O.HCl

Found C 62.71, H 4.99, N 10.88, F 9.94

Requires C 62.46, H 4.99, N 10.40, F 9.41

EXAMPLE 18 N-(3-(Pentafluorobenzyloxy)-2-pyridyl)phenylacetamidinehydrochloride (i) 2-Amino-3-(pentafluorobenzyloxy)pyridine.

To a solution of 2-amino-3-hydroxypyridine (8.1 g, 73.6 mmol) indichloromethane (65 ml) and 40% sodium hydroxide (65 ml) was addedAdogen 464 (5 ml) and alpha -bromo-2,3,4,5,6-pentafluorotoluene (20 g,81 mmol) with vigorous stirring. The mixture was stirred at roomtemperature for 16 hours and the resulting solid was filtered off,washed and dried to yield the title compound (14 g), m.p.130°-134° C.

(ii) N-(3-(Pentafluorobenzyloxy)-2-pyridyl)phenylacetamidinehydrochloride

2-Amino-3-pentafluorobenzyloxypyridine (11 g, 37.8 mmol) and ethylphenylacetimidate hydrochloride (9.07 g, 45.4 mmol) in ethanol (350 ml)were heated under reflux for 3 hrs. After evaporation of the solvent,the residue was purified by flash chromatography (silica, 1%methanol/dichloromethane) and trituration with ether to give the titlecompound (4.0 g), m.p. 189° C.

C₂₀ H₁₄ N₃ OF₅.HCl

Found C 54.12, H 3.46, N 9.44

Requires C 54.13, H 3.41, N 9.47

EXAMPLE 19N-(3-(2-Chloro-4,5-methylenedioxybenzyloxy)-2-pyridyl)phenylacetamidinehydrochloride (i)2-Amino-3-(2-chloro-4,5-methylenedioxybenzyloxy)-pyridine

To a solution of 2-amino-3-hydroxypyridine (9.75 g, 0.0886 mol) indichloromethane (55 ml) and 40% sodium hydroxide (55 ml) was addedAdogen 464 (5 ml) and 6-chloropiperonyl chloride (20 g, 0,0975 mol) withvigorous stirring. The mixture was stirred at room temperature for 16hours. Water (55 ml) was added and the mixture extracted withdichloromethane. The combined organic layers were dried and evaporated,and the residue purified by flash chromatography (silica, 1%methanol/dichloromethane) and trituration with ether to yield the titlecompound (6 g), m.p. 100°-104° C.

(ii)N-(6-Chloro-4,5-methylenedioxybenzyloxy)-2-pyridyl)phenylacetamidinehydrochloride

2-Amino-3-(6-chloro-4,5-methylenedioxybenzyloxy)pyridine (6 g, 21.6mmol) and ethyl phenylacetimidate hydrochloride (5.17 g, 26 mmol) inethanol (150 ml) were heated under reflux for 3 hrs. The solvent wasevaporated and the residue purified by flash chromatography (silica, 1%methanol/dichloromethane), trituration with ether and recrystallisationfrom ethanol to give the tire compound (1.0 g), m.p. 189° C. (softening170° C.).

C₂₁ H₁₈ ClN₃ O₃.HCl.0.4H₂ O

Found C 57.44, H 4.55, N 9.66

Requires C 57.38, H 4.54, N 9.56

EXAMPLE 20 N-(3-(2-Chlorobenzyloxy)-2-pyridyl)phenylacetamidinehydrochloride (a) 2-Amino-3-(2-chlorobenzyloxy)pyridine

A mixture of 2-chlorobenzyl chloride (47.6 g, 0.296 mol) and2-amino-3-hydroxypyridine (29.6 g, 0.269 mol) in 40% aqueous sodiumhydroxide solution (200 ml) and dichloromethane (200 ml) was treatedwith Adogen 464 (5 ml) and stirred vigorously at room temperature for 16hours. A further 200 ml of water was added and the product extractedinto dichloromethane, dried, the solvent evaporated and the residuetriturated with petroleum ether to obtain the product (32 g, 46%), m.p.95°-100° C.

(b) N-(3-(2-Chlorobenzyloxy)-2-pyridyl)phenylacetamidine hydrochloride

A mixture of 2-amino-3-(2-chlorobenzyloxy)pyridine (4.69 g, 20 mmol) andethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80ml) was heated under reflux for 2 hours. Evaporation of the solvent gavean oil which was purified by flash chromatography (chloroform/methanol)to obtain the product (0.97 g), m.p. 149°-155° C.

C₂₀ H₁₈ ClN₃ O.0.92HCl.0.9H₂ O

Found C 59.95, H 5.03, N 10.51, Cl 16.97

Requires C 59.80, H 5.20, N 10.40, Cl 16.97

EXAMPLE 21 N-(3-(2-Bromobenzyloxy)-2-pyridyl)phenylacetamidine (a)2-Amino-3-(2-bromobenzyloxy)pyridine

A mixture of 2-bromobenzyl bromide (50 g, 0.20 mol) and2-amino-3-hydroxypyridine (20.0 g, 0.18 mol) in 40% aqueous sodiumhydroxide solution (200 ml) and dichloromethane (200 ml) was treatedwith Adogen 464 (5 ml) and stirred vigorously at room temperature for 16hours. A further 200 ml of water was added and the product extractedinto dichloromethane, dried, and the solvent evaporated to obtain theproduct (35.4 g, 63%), m.p. 99°-100° C.

(b) N-(3-(2-Bromobenzyloxy)-2-pyridyl)phenylacetamidine

A mixture of 2-amino-3-(2-bromobenzyloxy)pyridine (5.58 g, 20 mmol) andethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80ml) was heated under reflux for 2 hours. Evaporation of the solvent gavea residue which was purified by chromatography (silica,chloroform/methanol) and recrystallisation from ethanol/ether to obtainthe product (0.28 g), m.p. 158°-169° C.

C₂₀ H₁₈ BrN₃ O.0.9HCl.0.7H₂ O

Found C 54.13, H 4.53, N 9.64, Br 18.46

Requires C 54.38, H 4.63, N 9.51, Br 18.09

EXAMPLE 22 N-(3-(2-Chloro-6-fluorobenzyloxy)-2-pyridyl)phenylacetamidinehydrochloride (a) 2-Amino-3-(2-chloro-6-fluorobenzyloxy)pyridine

A mixture of 2-chloro-6-fluorobenzyl chloride (52.9 g, 0.296 mol) and2-amino-3hydroxypyridine (29.6 g, 0,269 mol) in 40% aqueous sodiumhydroxide solution (200 ml) and dichloromethane (200 ml) was treatedwith Adogen 464 (5 ml) and stirred vigorously at room temperature for 16hours. A further 200 ml of water was added and the product extractedinto dichloromethane, dried, and the solvent evaporated to obtain theproduct (46.7 g, 62%), m.p. 123°-130° C.

(b) N-(3-(2-Chloro-6-fluorobenzyloxy)-2-pyridyl)phenyl-acetamidinehydrochloride

A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (5.05 g, 20mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) inethanol (80 ml) was heated under reflux for 2 hours. Evaporation of thesolvent gave an oil which was purified by flash chromatography(chloroform/methanol) and recrystallisation from ethanol/ether to obtainthe product (1.53 g), m.p. 115°-123° C.

C₂₀ H₁₉ ClFN₃ O.HCl.0.68H₂ O

Found C 57.38, H 4.62, N 10.12, Cl 16.85, F 4.34

Requires C 57.40, H 4.66, N 10.04, Cl 16.94, F 4.54

EXAMPLE 23 N-(3-(2-Trifluoromethylbenzyloxy)-2-pyridyl)phenylacetamidinehydrochloride (a) 2-Amino-3-(2-trifluoromethylbenzyloxy)pyridine

A mixture of 2-trifluoromethylbenzyl chloride (50 g, 0.257 mol) and2-amino-3hydroxypyridine (25.2 g, 0.233 mol) in 40% aqueous sodiumhydroxide solution (200 ml) and dichloromethane (200 ml) was treatedwith Adogen 464 (5 ml) and stirred vigorously at room temperature for 16hours. A further 200 ml of water was added and the product extractedinto dichloromethane, dried, and the solvent evaporated to obtain theproduct (45.3 g, 66%), m.p. 105°-110° C.

(b) N-(3-(2-Trifluoromethylbenzyloxy)-2-pyridyl)phenyl-acetamidinehydrochloride

A mixture of 2-amino-3-(2-trifluoromethylbenzyloxy)pyridine (5.36 g, 20mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) inethanol (80 ml) was heated under reflux for 2 hours. Evaporation of thesolvent gave an oil which was purified by flash chromatography(chloroform/methanol) and recrystallisation from ethanol/ether to obtainthe product (0.41 g), m.p. 105°-112° C.

C₂₁ H₁₈ F₃ N₃ O₂.0.85HCl.2H₂ O

Found C 55.67, H 4.60, N 9.64, Cl 6.53, F 12.79

Requires C 55.60, H 5.06, N 9.26, Cl 6.62, F 12.56

EXAMPLE 24 N-(3-(2-Fluorobenzyloxy)-2-pyridyl)phenylacetamidinehydrochloride (a) 2-Amino-3-(2-fluorobenzyloxy)pyridine

A mixture of 2-fluorobenzyl chloride (50 g, 0.346 mol) and2-amino-3-hydroxypyridine (39 g, 0.3 15 mol) in 40% aqueous sodiumhydroxide solution (200 ml) and dichloromethane (200 ml) was treatedwith Adogen 464 (5 ml) and stirred vigorously at room temperature for 16hours. A further 200 ml of water was added and the product extractedinto dichloromethane, dried, and the solvent evaporated to obtain theproduct (54.9 g, 80%), m.p. 85°-86° C.

(b) N-(3-(2-Fluorobenzyloxy)-2-pyridyl)phenylacetamidine hydrochloride

A mixture of 2-amino-3-(2-fluorobenzyloxy)pyridine (4.36 g, 20 mmol) andethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80ml) was heated under reflux for 2 hours. Evaporation of the solvent gavean oil which was purified by flash chromatography (chloroform/methanol)and recrystallisation from ethanol/ether to obtain the product (0.36 g),m.p. 160°-165° C.

C₂₀ H₁₈ FN₃ O.HCl

Found C 64.70, H 5.24, N 11.48, Cl 9.26, F 5.13

Requires C 64.60, H 5.15, N 11.30, Cl 9.53, F 5.11

EXAMPLE 25 N-(3-(1-Phenylethoxy)-2-pyridyl)phenylacetamidinehydrochloride (a) 2-Amino-3-(1-phenylethoxy)pyridine

A mixture of 1-bromoethylbenzene (55 g, 0.296 mol) and2-amino-3-hydroxypyridine (29.6 g, 0.269 mol) in 40% aqueous sodiumhydroxide solution (200 ml) and dichloromethane (200 ml) was treatedwith Adogen 464 (10 ml) and stirred vigorously at room temperature for16 hours. A further 200 ml of water was added and the product extractedinto dichloromethane, dried, and the solvent evaporated. Chromatography(silica gel, chloroform-methanol) gave the product as a crystallinesolid (37.6 g, 63%), m.p. 79°-83° C.

(b) N-(3-(1-Phenylethoxy)-2-pyridyl)phenylacetamidine hydrochloride

A mixture of 2-amino-3-(1-phenylethoxy)pyridine (4.28 g, 20 mmol) andethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80ml) was heated under reflux for 2 hours. Evaporation of the solvent gavea residue which was purified by chromatography (silica,chloroform/methanol) to obtain the product (1.05 g), m.p. 75°-80° C.

C₂₁ H₂₁ N₃ O.0.8HCl.0.5HCl

Found C 68.51, H 6.05, N 11.33, Cl 7.66

Requires C 68.24, H 6.21, N 11.37, Cl 7.67

EXAMPLE 26N-(3-(2,6-Dichlorobenzyloxy)-6-methyl-2-pyridyl)phenylacetamidinehydrochloride (a) 2-Amino-3-hydroxy-6-methylpyridine

3-Hydroxy-6-methyl-2-nitropyridine (25 g, 0.162 g) was dissolved inethanol (600 ml) and hydrogenated over 10% palladium-charcoal (3.3 g) at50 p.s.i. Removal of the catalyst and evaporation of the solvent gavethe product (36.4 g, 91%), m.p. 147°-149° C.

(b) 2-Amino-3-(2,6-dichlorobenzyloxy)-6-methylpyridine

A mixture of 2,6-dichlorobenzyl bromide (26.3 g, 0.11 mol) and2-amino-3-hydroxy-6methylpyridine (12.4 g, 0.1 mol) in 40% aqueoussodium hydroxide solution (200 ml) and dichloromethane (200 ml) wastreated with Adogen 464 (10 ml) and stirred vigorously at roomtemperature for 16 hours. A further 200 ml of water was added and theproduct extracted into dichloromethane, dried, and the solventevaporated to obtain the product (21.4 g, 7 6%), m.p. 135°-137° C.

(c) N-(3-(2,6-Dichlorobenzyloxy)-6-methyl-2-pyridyl)phenyl-acetamidinehydrochloride

A mixture of 2-amino-3-(2,6-dichlorobenzyloxy)-6-methyl-pyridine (5.66g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol)in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation ofthe solvent gave a residue which was purified by chromatography (silica,chloroform/methanol) and recrystallisation from ethanol/ether to obtainthe product (1.34 g), m.p. 217°-218° C.

C₂₁ H₁₉ Cl₂ N₃ O.HCl

Found C 57.71, H 4.63, N 9.61, Cl 23.93

Requires C 57.75, H 4.62, N 9.62, Cl 24.35

EXAMPLE 27N-(3-(2,6-Difluorobenzyloxy)-6-methyl-2-pyridyl)phenylacetamidinehydrochloride (a) 2-Amino-3-(2,6-difluorobenzyloxy)-6-methylpyridine

A mixture of 2,6-difluorobenzyl bromide (25 g, 0.12 1 mol) and2-amino-3-hydroxy-6methylpyridine (13.6 g, 0.11 mol) in 40% aqueoussodium hydroxide solution (200 ml) and dichloromethane (200 ml) wastreated with Adogen 464 (10 ml) and stirred vigorously at roomtemperature for 16 hours. A further 200 ml of water was added and theproduct extracted into dichloromethane, dried, and the solventevaporated to obtain the product (25.8 g, 94%), m.p. 121°-123° C.

(b) N-(3-(2,6-Difluorobenzyloxy)-6-methyl-2-pyridyl)phenyl-acetamidinehydrochloride

A mixture of 2-amino-3-(2,6-difluorobenzyloxy)-6-methyl-pyridine (5.0 g,20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) inethanol (80 ml) was heated under reflux for 2 hours. Evaporation of thesolvent gave an oil which was purified by chromatography (silica,chloroform/methanol) and recrystallisation from ethanol/ether to obtainthe product (0.56 g), m.p. 173°-177° C.

C₂₁ H₁₉ F₂ N₃ O.0.96HCl.0.4H₂ O

Found C 61.54, H 5.00, N 10.34, Cl 8.31, F 9.33

Requires C61.59, H5.10, N 10.26, Cl 8.31, F9.27

EXAMPLE 28 N-(3-(2,4-Dichlorobenzyloxy)-2-pyridyl)phenylacetamidinehydrochloride (a) 2-Amino-3-(2,4-dichlorobenzyloxy)pyridine

A mixture of 2,4-dichlorobenzyl bromide (15 g, 76.7 mmol) and2-amino-3hydroxypyridine (7.7 g, 69.7 mmol) in 40% aqueous sodiumhydroxide solution (52 ml) and dichloromethane (52 ml) was treated withAdogen 464 (5 ml) and stirred vigorously at room temperature for 16hours. More water was added and the product extracted intodichloromethane, dried, and the solvent evaporated to obtain the productafter trituration with ether (13.3 g, 70%), m.p. 120°-121° C.

(b) N-(3-(2,4-Dichlorobenzyloxy)-2-pyridyl)phenyl-acetamidinehydrochloride

A mixture of 2-amino-3-(2,4-dichlorobenzyloxy)pyridine (5.07 g, 18.8mmol) and ethyl phenylacetimidate hydrochloride (3.52 g, 25.8 mmol) inethanol (150 ml) was heated under reflux for 2 hours. Evaporation of thesolvent gave an oil which was purified by flash chromatography(dichloromethane/methanol) and trituration with ether to obtain theproduct (0.59 g), m.p. 185°-187° C.

C₂₀ H₁₇ Cl₂ N₃ O.HCl

Found C 56.47, H 4.41, N 10.01

Requires C 56.82, H 4.29, N 9.94

EXAMPLE 29 N-(3-(2,5-Dichlorobenzyloxy)-2-pyridyl)phenylacetamidinehydrochloride (a) 2-Amino- 3-(2,5-dichlorobenzyloxy)pyridine

A mixture of 2,5-dichlorobenzyl bromide (14.8 g, 75.9 mmol) and2-amino-3hydroxypyridine (7.7 g, 69.7 mmol) in 40% aqueous sodiumhydroxide solution (52 ml) and dichloromethane (52 ml) was treated withAdogen 464 (5 ml) and stirred vigorously at room temperature for 16hours. More water was added and the product extracted intodichloromethane, dried, and the solvent evaporated to obtain the productafter trituration with ether (8.6 g, 46%), m.p. 103°-104 ° C.

(b) N-(3-(2,5-Dichlorobenzyloxy)-2-pyridyl)phenyl-acetamidinehydrochloride

A mixture of 2-amino-3-(2,5-dichlorobenzyloxy)pyridine (5.08 g, 18.8mmol) and ethyl phenylacetimidate hydrochloride (3.52 g, 25.5 mmol) inethanol (150 ml) was heated under reflux for 2 hours, then evaporated.Flash chromatography (dichloromethane/methanol) and trituration withether gave the product (0.25 g), m.p. 191°-193° C.

C₂₀ H₁₇ Cl₂ N₃ O.HCl.0.5H₂ O

Found C 55.67, H 4.41, N 10.02

Requires C 55.63, H 4.44, N 9.73

EXAMPLE 30 N-(3-Benzyloxy-2-pyridyl)-.N'-phenylguanidine (a)N-(3-Benzyloxy-2-pyridyl)-N'-phenylthiourea

A mixture of 2-amino-3-benzyloxypyridine (5.0 g, 25 mmol), phenylisothiocyanate (3.72 g, 25 mmol) and toluene (20 ml) was heated atreflux for 1.5 hours, then left at room temperature overnight. Thesolution was diluted with ether, and the product filtered off; yield 5.6g (67%), m.p. 107°-109° C.

(b) N-(3-Benzyloxy-2-pyridyl)-N'-phenylguanidine

A mixture of N-(3-Benzyloxy-2-pyridyl)-N'-phenylthiourea (1.0 g, 2.9mmol) and yellow mercuric oxide (1.6 g, 7.4 mmol) was stirred inethanolic ammonia (20 ml) at room temperature for 18 hours, then heatedat reflux for 30 rains. After cooling, the black solid was filtered offand the filtrate evaporated to an oil, which crystallised on triturationwith ether/pet. ether. Chromatography (silica, 1-3% methanolic ammoniain dichloromethane) and trituration with pet. ether gave the product(0.49 g, 51%), m.p. 115°-119° C.

C₁₉ H₁₈ N₄ O

Found C 71.40, H 5.72, N 17.50

Requires C 71.68, H 5.70, N 17.60

EXAMPLE 31N-[3-(2-Chloro-6-fluorobenzyloxy)pyrid-2-yl]-2-chiorophenylacetamidinehydrochloride (a) Ethyl 2-chlorophenylacetimidate hydrochloride

A solution of 2-chlorobenzyl cyanide (32.4 g, 0.214 mol) in ethanol (70ml) was cooled to 5 ° C., then HCl gas was passed through with stirringfor 30 minutes and the resultant mixture was allowed to stand at roomtemperature for 18 hours. Evaporation of the solvent and triturationwith ether gave the desired product, which was used immediately withoutfurther purification. Yield 49.0 g (98%).

(b)N-[3-(2-Chloro-6-fluorobenzyloxy)pyrid-2-yl]-2-chlorophenylacetamidinehydrochloride

A mixture of ethyl 2-chlorophenylacetimidate hydrochloride (5.07 g,0.0216 mol), 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (4.95 g,0.0196 mol)and ethanol (150 ml) was heated under reflux for 2 hours. Thesolvent was evaporated off and the resultant oil was purified bychromatography (silica gel, 1% methanol/dichloromethane) and triturationwith ether. Yield 0.7 g (8%), m.p. 156°-158 ° C.

C₂₀ H₁₆ Cl₂ FN₃ O.HCl.2.1H₂ O

Found C 49.83, H 4.29, N 8.77

Expected C 49.50, H 4.49, N 8.53

EXAMPLE 32 N-(3-Benzyloxy-2-pyridyl)-N'-(4-chlorophenyl)guanidine (a)N-(3-Benzyloxy-2-pyridyl)-N'-(4-chlorophenyl)thiourea

A stirring mixture of 2-amino-3-benzyloxy pyridine (5.37 g, 0.0268 mol)and 4-chlorophenylisothiocyanate (5 g, 0.0295 mol) in toluene (20 ml)was heated under reflux for 2 h. After allowing to cool, the solutionwas treated with ether, and the resulting solid filtered off, washed anddried. Yield 8.33 g (84%), m.p. 140°-143 ° C.

(b) N-(3-Benzyloxy-2-pyridyl)-N'-(4-chlorophenyl)guanidine

To a stirring suspension ofN-(3-benzyloxy-2-pyridyl)-N'-(4-chlorophenyl)thiourea (1.5 g, 0.00406mol) in ammonia-saturated methanol (30 ml) was added yellow mercuricoxide (2.2 g, 0.01 mol). Stirring was continued for 20 h, then thesolvent evaporated and the black residue treated with chloroform andfiltered through celite. The filtrate was evaporated to a whim solid,which was recrystallised from ethyl acetam. Yield 0.76 g (53%), m.p.170°-172 ° C.

C₁₉ H₁₇ ClN₄ O

Found C 64.97, H 4.89, N 16.04

Expected C 64.68, H 4.86, N 15.88

EXAMPLE 33 N-(3-Benzyloxy-2-pyridyl)-N'-(4-cyanophenyl)guanidine (a)N-(3-Benzyloxy-2-pyridyl)-N'-(4-cyanophenyl)thiourea

A stirring mixture of 2-amino-3-benzyloxy pyridine (5.68 g, 0.0284 mol)and 4cyanophenyl isothiocyanate (5 g, 0.0312 mol) in toluene (20 ml) washeated under reflux for 2 h. After allowing to cool, the solution wastreated with ether, and the resulting solid filtered off, washed anddried. Yield 9.4 g (92%), m.p. 163°-165 ° C.

(b) N-(3-Benzyloxy-2-pyridyl)-N'-(4-cyanophenyl)guanidine

To a stirring suspension ofN-(3-benzyloxy-2-pyridyl)-N'-(4-cyanophenyl)thiourea (2 g, 0.0055 mol)in ammonia-saturated methanol (40 ml) was added yellow mercuric oxide (3g, 0.014 mol). Stirring was continued for 20 h, then the mixturefiltered through celite, and the solid washed several times withchloroform. The filtrate was evaporated to a white solid, which wastriturated with ether. Yield 1.12 g (59%), m.p. 173°-175 ° C.

C₂₀ H₁₇ N₅ O

Found C 69.79, H 4.94, N 20.44

Expected C 69.96, H 4.99, N 20.39

EXAMPLE 34N-(3-Benzyloxypyrid-2-yl)-N'-(4-trifluoromethylphenyl)guanidine (a)N-(3-Benzyloxypyrid-2-yl)-N'-(4-trifluoromethylphenyl)thiourea

A mixture of 2-amino-3-benzyloxypyridine (2.34 g, 0.0117 mol),4-trifluoromethylphenyl isothiocyanate (2.85 g, 0.014 mol) and toluene(10 ml) was refluxed for 3.5 hours, then cooled and treated with etherto induce crystallisation of the product. Yield 3.06 g (65%), m.p.165°-167 ° C.

(b) N-(3-Benzyloxypyrid-2-yl)-N'-(4-trifluoromethylphenyl)guanidine

A mixture ofN-(3-benzyloxypyrid-2-yl)-N'-(4-trifluoromethylphenyl)thiourea (3.08 g,0.0076 mol), yellow mercuric oxide (2 g, 0.0092 mol) and methanolicammonia solution (40 ml) was stirred for 48 hours at room temperature,then the solvent was removed in vacuo and the residue extracted withboiling chloroform and filtered hot. Evaporation of the filtrate andrecrystallisation from acetonitrile gave the desired product. Yield 2.05g (70%), m.p. 154°-155 ° C.

C₂₀ H₁₇ F₃ N₄ O

Found C 62.18, H 4.61, N 14.56

Expected C 62.17, H 4.43, N 14.50

EXAMPLE 35 N-(3-Benzyloxy)pyrid-2-yl-N'-(3,4-dichlorophenyl)guanidine(a) N-(3-Benzyloxypyrid-2-yl)-N'-(3,4-dichlorophenyl)thiourea

A mixture of 2-amino-3-benzyloxypyridine (2.14 g, 0.011 mol),3,4-dichlorophenyl isothiocyanate (2.62 g, 0.013 mol) and toluene (10ml) was refluxed for 3.5 hours, then cooled and treated with ether toinduce crystallisation of the product. Yield 3.64 g (84%), m.p. 144°-146° C.

(b) N-(3-Benzyloxypyrid-2-yl)-N'-(3,4-dichlorophenyl)guanidine

A mixture of N-(3-benzyloxypyrid-2-yl)-N'-(3,4-dichlorophenyl)thiourea(3.59 g, 0.009 mol), yellow mercuric oxide (2.34 g, 0.011 mol) andmethanolic ammonia (40 ml) was stirred for 2 days at room temperature.The solvent was removed in vacuo and the black residue was boiled withchloroform and filtered hot. Evaporation of the solvent andrecrystallisation from acetonitrile gave the desired product. Yield 2.44g (70%), m.p. 161°-162 ° C.

C₁₉ H₁₆ Cl₂ N₄ O

Found C 58.61, H 4.25, N 14.34

Expected C 58.93, H 4.16, N 14.47

EXAMPLE 36 N-[3-(2-Methylbenzyloxy)pyrid-2-yl]-N'-phenylguanidine (a)N-[3-(2-Methylbenzyloxy)pyrid-2-yl]-N'-phenylthiourea

A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (1.67 g, 0.0078 mol),phenyl isothiocyanate (1.26 g, 0.0093 mol) and toluene (10 ml) wasrefluxed for 3.5 hours, then cooled and treated with ether to inducecrystallisation of the product. Yield 1.8 g (66%), m.p. 150°-151 ° C.

(b) N-[3-(2-Methylbenzyloxy)pyrid-2-yl]-N'-phenylguanidine

A mixture of N-[3-(2-methylbenzyloxy)pyrid-2-yl]-N'-phenylthiourea (1.76g, 0.005 mol), yellow mercuric oxide (1.31 g, 0.006 mol) and methanolicammonia (40 ml) was stirred for 3 days at room temperature. The solventwas removed in vacuo and the black residue was boiled with chloroformand filtered hot. Evaporation of the solvent and recrystallisation fromacetonitrile gave the desired product. Yield 1.2 g (72%), m.p. 157°-158° C.

C₂₀ H₂₀ N₄ O

Found C 72.29, H 6.11, N 16.85

Expected C 72.27, H 6.06, N 16.85

EXAMPLE 37 N-[3-(2- Methylbenzyloxy)pyrid- 2-yl]-N'-(4-chlorophenyl)guanidine (a)N-[3-(2-Methylbenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea

A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (1.19 g, 0.0056 mol),4-chlorophenyl isothiocyanate (1.15 g, 0.0068 mol) and toluene (10 ml)was refluxed for 2.5 hours, then cooled and treated with ether to inducecrystallisation of the product. Yield 1.63 g (77%), m.p. 181°-183 ° C.

(b) N-[3-(2-Methylbenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)guanidine

A mixture ofN-[3-(2-methylbenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (0.99 g,0.0026 mol), yellow mercuric oxide (0.67 g, 0.003 mol) and methanolicammonia solution (40 ml) was stirred at room temperature for 48 hours.The solvent was removed in vacuo and the black residue was boiled withchloroform and filtered hot. Evaporation of the solvent andrecrystallisation from acetonitrile gave the desired product. Yield 0.59g (62%), m.p. 158°-159 ° C.

C₂₀ H₁₉ ClN₄ O

Found C 65.46, H 5.26, N 15.34

Expected C 65.48, H 5.22, N 15.27

EXAMPLE 38 N-[3-(2-Fluorobenzyl)pyrid-2-yl]-N'-(4-chlorophenyl)guanidine(a) N-[3-(2-Fluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea

A mixture of 2-amino-3-(2-fluorobenzyloxy)pyridine (1.98 g, 0.0091 mol),4chlorophenyl isothiocyanate (1.83 g, 0.011 mol) and toluene (10 ml) wasrefluxed for 3.5 hours, cooled and treated with diethyl ether to inducecrystallisation of the product. Yield 1.98 g (56%), m.p. 141°-143

(b) N-[3-(2-Fluorobenzyl)pyrid-2-yl]-N'-(4-chlorophenyl)guanidine

A mixture of yellow mercuric oxide (1.35 g, 0.0062 mol),N-[3-(2-fluorobenzyloxy)pyrid2-yl]-N'-(4-chlorophenyl)thiourea (1.98 g,0.005 1 mol) and methanolic ammonia solution (40 ml) was stirred for 2days at room temperature. The solvent was removed in vacuo and the blackresidue was boiled with chloroform and filtered hot. Evaporation of thesolvent and recrystallisation from acetonitrile gave the desiredproduct. Yield 0.34 g (18%), m.p. 175°-176° C.

C₁₉ H₁₆ ClFN₄ O

Found C 61.30, H 4.48, N 14.99

Expected C 61.54, H 4.35, N 15.11

EXAMPLE 39N-[3-(2-Chlorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)guanidine (a)N-[3-(2-Chlorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea

A mixture of 2-amino-3-(2-chlorobenzyloxy)pyridine (1.81 g, 0.0077 mol),4chlorophenyl isothiocyanate (1.59 g, 0.0094 mol) and toluene (10 ml)was refluxed for 2.5 hours, cooled and treated with diethyl ether toinduce crystallisation of the product. Yield 2.54 g (90%), m.p. 177° 179° C.

(b) N-[3-(2-Chlorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)guanidine

A mixture of yellow mercuric oxide (1.06 g, 0.0049 mol),N-[3-(2-chlorobenzyloxy)pyrid2-yl]-N'-(4-chlorophenyl)thiourea (1.56 g,0,004 mol) and methanolic ammonia solution (40 ml) was stirred for 2days at room temperature. The solvent was removed in vacuo and the blackresidue was boiled with chloroform and filtered hot. Evaporation of thesolvent and recrystallisation from acetonitrile gave the desiredproduct. Yield 0.72 g, (46%),m.p. 162°-163 ° C.

C₁₉ H₁₆ Cl₂ N₄ O

Found C 58.78, H 4.31, N 14.47

Expected C 58.93, H 4.16, N 14.47

EXAMPLE 40N-[3-(4-Methylbenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)guanidine a)2-Amino-3-(4-methylbenzyloxy)pyridine

A mixture of 2-amino-3-hydroxypyridine (2.7 g, 0.024 mol),dichloromethane (40 ml) and 40% aqueous sodium hydroxide solution (40ml) was stirred for 5 rains, then 4methylbenzyl bromide (4.51 g, 0.024mol) and Adogen 464 (3 ml) were added and stirring was continued for 16hours. The mixture was diluted with water and extracted withdichloromethane (×2), and the combined organic layers dried, evaporated,and triturated with ether. Yield 2.92 g (56%), m.p. 123° 125 ° C.

(b) N-[3-(4-Methylbenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea

A mixture of 2-amino-3-(4-methylbenzyloxy)pyridine (1.45 g, 0.0068 mol),4chlorophenyl isothiocyanate (1.38 g, 0.008 mol) and toluene (10 ml) wasrefluxed for 3.5 hours, then cooled and treated with diethyl ether toinduce crystallisation of the product. Yield 1.8 g (70%), m.p. 145°-147° C.

(c) N-[3-(4-Methylbenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)guanidine

A mixture of yellow mercuric oxide (0.68 g, 0.0031 mol),N-[3-(4-methylbenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (1.01 g,0.0026 mol) and methanolic ammonia solution (40 ml) was stirred for 2days at room temperature. The solvent was removed in vacuo and the blackresidue was boiled with chloroform and filtered hot. Evaporation of thesolvent and recrystallisation from acetonitrile gave the desiredproduct. Yield 0.5 g (52%), m.p. 174°-175 ° C.

C₂₀ H₁₉ ClN₄ O

Found C 65.11, H 5.27, N 15.18

Expected C 65.48, H 5.22, N 15.27

EXAMPLE 41 N-[3-(4-Methoxybenzyloxy)pyrid-2-yl]-N'-phenylguanidine (a)N-[3-(4-Methoxybenzyloxy)pyrid-2-yl]-N'-phenylthiourea

A mixture of 2-amino-3-(4-methoxybenzyloxy)pyridine (1.91 g, 0.0083mol), phenyl isothiocyanate (1.4 g, 0.01 mol) and toluene (10 ml) wasrefluxed for 3.5 hours, then cooled and treated with diethyl ether toinduce crystallisation of the product. Yield 2.18 g (72%), m.p. 123°-125° C.

(b) N-[3-(4-Methoxybenzyloxy)pyrid-2-yl]-N'-phenylguanidine

A mixture of yellow mercuric oxide (1.51 g, 0.0069 mol),N-[3-(4-methoxybenzyloxy)pyrid-2-yl]-N'-phenylthiourea (2.14 g, 0.0058mol) and methanolic ammonia solution (40 ml) was stirred for 2 days atroom temperature. The solvent was removed in vacuo and the black residuewas boiled with chloroform and filtered hot. Evaporation of the solventfollowed by trituration with ether and recrystallisation fromacetonitrile gave the desired product. Yield 1.27 g (62%), m.p. 141°-143° C.

C₂₀ H₂₀ N₄ O₂

Found C 69.31, H 5.91, N 16.10

Expected C 68.95, H 5.79, N 16.08

EXAMPLE 42 N-(3-(4-Methoxybenzyloxy)pyrid-2-yl)-N'-(4-chlorophenyl)guanidine (a)N-(3-(4-Methoxybenzyloxy)pyrid-2-yl)-N'-(4-chlorophenyl)thiourea

A mixture of 2-amino-3-(4-methoxybenzyloxy)pyridine (1.80 g, 0.0078mol), 4chlorophenyl isothiocyanate (1.58 g, 0.0094 mol) and toluene (10ml) was refluxed for 3.5 hours, then cooled and treated with diethylether to induce crystallisation of the product. Yield 2.2 g (70.5%),m.p. 136°-138 ° C.

(b) N-(3-(4-Methoxybenzyloxy)pyrid-2-yl)-N'-(4-chlorophenyl)guanidine

A mixture of yellow mercuric oxide (1.05 g, 0.00488 mol),N-[3-(4-methoxybenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (1.5 g,0.0041 mol)and methanolic ammonia solution (40 ml) was stirred for 2days at room temperature. The solvent was removed in vacuo and the blackresidue was boiled with chloroform and filtered hot. Evaporation of thesolvent followed by trituration with ether and recrystallisation fromacetonitrile gave the desired product. Yield 0.96 g (61.5%) m.p.165°-166 ° C.

C₂₀ H₁₉ ClN₄ O₂

Found C 63.03, H 5.10, N 14.65, Cl 9.20

Expected C 62.75, H 5.00, N 14.63, C; 9.26

EXAMPLE 43 N-[3-(4-Chlorobenzyloxy)pyrid-2-yl]-N'-phenylguanidine (a)2-Amino-3-(4-chlorobenzyloxy)pyridine

A mixture of 2-amino-3-hydroxy pyridine (3.45 g, 0.313 mol),dichloromethane (20 ml) and 40% aqueous sodium hydroxide solution (20ml) was stirred for five minutes, then 2chlorobenzyl bromide (6.09 g,0.0315 mol) and Adogen 464 (3 ml) were added and stirring continued for16 hours. The mixture was diluted with water and extracted withdichloromethane. Drying and evaporation of the organic extracts, andtrituration with ether gave the desired product. Yield 3.5 g (48%), m.p.121°-123 ° C.

(b) N-[3-(4-Chlorobenzyloxy)pyrid-2-yl]-N'-phenylthiourea

A mixture of 2-amino-3-(4-chlorobenzyloxy)pyridine (3.37 g, 0,014 mol),phenyl isothiocyanate (2.33 g, 0,017 mol) and toluene (10 ml) wasrefluxed for 3.5 hours, then cooled and treated with diethyl ether toinduce crystallisation of the product. Yield 4.36 g (82%), m.p. 162°-164° C.

(c) N-[3-(4-Chlorobenzyloxy)pyrid-2-yl]-N'-phenylguanidine

A mixture of N-[3-(4-chlorobenzyloxy)pyrid-2-yl]-N'-phenylthiourea (3.00g, 0.008 mol), yellow mercuric oxide (2.17g, 0.01 mol) and methanolicammonia solution (40 ml) was stirred for 48 hours. The solvent wasremoved in vacuo and the black residue was boiled with chloroform andfiltered hot. Evaporation of the solvent and recrystallisation fromacetonitrile gave the desired product. Yield 1.8 g (63%), m.p. 173°-174° C.

C₁₉ H₁₇ ClN₄ O

Found C 64.39, H 5.00, N 15.92

Expected C 64.68, H 4.86, N 15.88

EXAMPLE 44N-[3-(2-Fluoro-6-chlorobenzyloxy)pyrid-2-yl]-N'-phenylguanidine (a)N-[3-(2-Fluoro-6-chlorobenzyloxy)pyrid-2-yl]-N'-phenylthiourea

A mixture of 2-amino-3-(2-fluoro-6-chlorobenzyloxy)pyridine (7.6 g, 0.03mol), phenyl isothiocyanate (3.95 ml, 0.033 mol) and toluene (25 ml) wasrefluxed for 2.5 hours, then cooled and treated with diethyl ether toinduce crystallisation of the product. Yield 8.47 g (73%), m.p. 143°-145° C.

(b) N-[3-(2-Fluoro-6-chlorobenzyloxy)pyrid-2-yl]-N'-phenylguanidine

A mixture ofN-[3-(2-fluoro-6-chlorobenzyloxy)pyrid-2-yl]-N'-phenylthiourea (2 g,0.0052 mol), yellow mercuric oxide (1.34g, 0.0062 mol) and methanolicammonia solution (40 ml) was stirred for 72 hours. The solvent wasremoved in vacuo and the black residue was treated with chloroform andfiltered through celite. Evaporation of the solvent andrecrystallisation from acetonitrile gave the desired product. Yield 1.07g (56%), m.p. 147°-149 ° C.

C₁₉ H₁₆ ClFN₄ O

Found C 61.51, H 4.39, N 15.15

Expected C 61.54, H 4.35, N 15.11

EXAMPLE 45N-[3-(2-Fluoro-6-chlorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)guanidine(a)N-[3-(2-Fluoro-6-chlorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea

A mixture of 2-amino-3-(2-fluoro-6-chlorobenzyloxy)pyridine (3.46 g,0.014 mol), 4chlorophenyl isothiocyanate (2.55 g, 0.015 mol) and toluene(10 ml) was refluxed for 2 hours, then cooled and treated with diethylether to induce crystallisation of the product. Yield 4.64 g (73%), m.p.162°-164 ° C.

(b)N-[3-(2-Fluoro-6-chlorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)guanidine

A mixture ofN-[3-(2-fluoro-6-chlorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea(2 g, 0.0047 mol), yellow mercuric oxide (2.56 g, 0.012 mol) andmethanolic ammonia solution (40 ml) was stirred for 40 hours. Thesolvent was removed in vacuo and the black residue was treated withchloroform and filtered through celite. Evaporation of the solvent andrecrystallisation from chloroform/ether gave the desired product. Yield0.96 g (50%), m.p. 168°-170 ° C.

C₁₉ H₁₅ Cl₂ FN₄ O

Found C 56.30, H 3.79, N 13.84

Expected C 56.31, H 3.73, N 13.82

EXAMPLE 46N-[3-(2-Chloro-6-fluorobenzyloxy)pyrid-2-yl]-N'-(2-fluorophenyl)guanidine(a)N-[3-(2-Chloro-6-fluorobenzyloxy)pyrid-2-yl]-N'-(2-fluorophenyl)thiourea

A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (7.48g, 0.03mol), 2fluorophenyl isothiocyanate (5.0 g, 0.033 mol) and toluene (30ml) was heated under reflux for 1.5 hours, then cooled and diluted withether to induce crystallisation of the product. Yield 7.9 g (59 %), m.p.145°-147 ° C.

(b)N-[3-(2-Chloro-6-fluorobenzyloxy)pyrid-2-yl]-N'-(2-fluorophenyl)guanidine

A mixture of yellow mercuric oxide (4.13g, 0.019 mol),N-[3-(2-chloro-6-fluoro-benzyloxy)pyrid-2-yl]-N'-(2-fluorophenyl)thiourea (3.10g, 0.0076 mol)and methanolic ammonia solution (60 ml) was stirred for 24 hours at roomtemperature. The mixture was filtered through celite and the filtrateevaporated to a yellow solid, which was recrystallised from ethylacetate/pet. ether. Yield 1.51 g (51%), m.p 138°-140 ° C.

C₁₉ H₁₅ ClF₂ N₄ O

Found C 58.73, H 3.91, N 14.40

Expected C 58.69, H 3.89, N 14.41

EXAMPLE 47 N-[3-(2-Chloro-6fluorobenzyloxy)pyrid-2-yl]-N'-(4-nitrophenyl)guanidine (a)N-[3-(2-Chloro-6 fluorobenzyloxy)pyrid-2-yl]-N'-(4-nitrophenyl)thiourea

A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (7.01g,0.028 mol), 4nitrophenyl isothiocyanate (5.31g, 0.03 mol) and toluene(50 ml) was heated under reflux for 2 hours, then cooled and treatedwith ether to induce crystallisation of the product. Yield 11.07 g(86%), m.p. 214° 215 ° C.

(b) N-[3-(2-Chloro-6fluorobenzyloxy)pyrid-2-yl]-N'-(4-nitrophenyl)guanidine

A mixture of yellow mercuric oxide (1.26g, 0.006 mol), N-[3-(2-chloro-6fluorobenzyloxy)pyrid-2-yl]-N'-(4-nitrophenyl)thiourea (2.08g, 0.005mol) and methanolic ammonia solution (40 ml) was stirred for 24 hours atroom temperature, then heated under reflux for 30 min. The solvent wasremoved in vacuo and the black residue was boiled with chloroform andfiltered hot. Evaporation of the solvent and recrystallisation fromethanol gave the desired product. Yield 1.16 g (58%), m.p 180°-182 ° C.

C₁₉ H₁₅ ClFN₅ O₃

Found C 54.84, H 3.71, N 16.83

Expected C 54.88, H 3.64, N 16.84

EXAMPLE 48N-[3-(2-Chloro-6-fluorobenzyloxy)pyrid-2-yl]-N'-(4-methylphenyl)guanidine(a)N-[3-(2-Chloro-6-fluorobenzyloxy)pyrid-2-yl]-N'-(4-methylphenyl)thiourea

A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (2g, 0.008mol), 4methylphenyl isothiocyanate (1.43g, 0.0096 mol) and toluene (10ml) was heated under reflux for 5 hours, then cooled and diluted withether to induce crystallisation of the product. Yield 2.61g (82%) m.p.138°-140 ° C.

(b)N-[3-(2-Chloro-6-fluorobenzyloxy)pyrid-2-yl]-N'-(4-methylphenyl)guanidine

A mixture of yellow mercuric oxide (0.65g, 0.0025 mol),N-[3-(2-chloro-6-fluorobenzyloxy)pyrid-2-yl]-N'-4-methylphenylthiourea(1 .0g, 0.0025 mol) and methanolic ammonia solution (30 ml) was stirredfor 3 days at room temperature. The solvent was removed in vacuo and theblack residue was boiled with chloroform and filtered hot. Evaporationof the solvent followed by recrystallisation from ethanol gave thedesired product. Yield 0.55 g, (57%), m.p. 136°-138 ° C.

C₂₀ H₁₈ N₄ ClFO

Expected C 62.42, H 4.71, N 14.56

Found C 62.57, H 4.81, N 14.66

EXAMPLE 49N-[3-(2-Chloro-6-fluorobenzyloxy)pyrid-2-yl]-N'-(4-fluorophenyl)guanidine(a)N-[3-(2-Chloro-6-fluorobenzyloxy)pyrid-2-yl]-N'-(4-fluorophenyl)thiourea

A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (2g, 0.008mol), 4fluorophenyl isothiocyanate (1.45g, 0.0096 mol) and toluene (10ml) was heated under reflux for 5 hours, then cooled and diluted withether to induce crystallisation of the product. Yield 2.31 g (71%), m.p.146°-148 ° C.

(b)N-[3-(2-Chloro-6-fluorobenzyloxy)pyrid-2-yl]-N'-(4-fluorophenyl)guanidine

A mixture of yellow men:uric oxide (0.65g, 0.003 mol),N-[3-(2-chloro-6-fluorobenzyloxy)pyrid-2-yl]-N'-4-fluorophenylthiourea(1 .0g, 0.0025 mol) and methanolic ammonia solution (30 ml) was stirredfor 3 days at room temperature. The solvent was removed in vacuo and theblack residue was boiled with chloroform and filtered hot. Evaporationof the solvent followed by recrystallisation from ethanol gave thedesired product. Yield 0.38 g, (40%), m.p. 152°-154 ° C.

C₁₉ H₁₅ ClF₂ N₄ O

Expected C58.69, H3.89, N 14.41, Cl 9.12

Found C 58.62, H 4.05, N 14.49, Cl 9.14

EXAMPLE 50 N-[3-(2-Chloro-6-fluorobenzyloxy)pyrid-2-yl]-N'-(2-methyl-4

chlorophenyl)guanidine

(a)N-[3-(2-Chloro-6-fluorobenzyloxy)pyrid-2-yl]-N'-(2-methyl-4chlorophenyl)thiourea

A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)pyridine (2 g, 0.008mol), (2-methyl-4-chlorophenyl isothiocyanate (1.76 g, 0.0096 mol) andtoluene (10 ml) was heated under reflux for 5 hours, then cooled anddiluted with ether to induce crystallisation of the product. Yield 2.72g(77%), m.p. 176°-177 ° C.

(b)N-[3-(2-Chloro-6-fluorobenzyloxy)pyrid-2-yl]-N'-(2-methyl-4chlorophenyl)guanidine

A mixture of yellow mercuric oxide (0.6 g, 0.0028 mol),N-[3-(2-chloro-6-fluorobenzyloxy)pyrid-2-yl]-N'-2-methyl-4-chlorophenylthiourea(1.0 g, 0.0023 mol) and methanolic ammonia solution (30 ml) was stirredfor 3 days at room temperature. The solvent was removed in vacuo and theblack residue was boiled with chloroform and filtered hot. Evaporationof the solvent followed by recrystallisation from ethanol gave thedesired product. Yield 0.63 g (65%), m.p. 155°-156 ° C.

C₂₀ H₁₇ Cl₂ FN₄ O

Expected C 57.29, H 4.09, N 13.36, Cl 16.91

Found C 57.42, H 4.20, N 13.53, Cl 17.33

EXAMPLE 51 N-[3-(2,6-Dichiorobenzyloxy)pyrid-2-yl]-N'-phenylguanidine(a) N-[3-(2,6-Dichlorobenzyloxy)pyrid-2-yl]-N'-phenylthiourea

A mixture of 2-amino-3-(2,6-dichlorobenzyloxy)pyridine (2 g, 0.007 1mol), phenyl isothiocyanate (1.15 g, 0.0085 mol) and toluene (10 ml) washeated under reflux for 1.5 hours, then cooled and diluted with ether toinduce crystallisation of the product, which was recrystallised fromethanol/ether. Yield 1.2 g (42%), m.p. 148°-149 ° C.

(b) N-[3-(2,6-Dichlorobenzyloxy)pyrid-2-yl]-N'-phenylguanidine

A mixture of yellow mercuric oxide (0.62 g, 0.0029 mol),N-[3-(2-,6-dichlorobenzyloxy)pyrid-2-yl]-N'-phenylthiourea (1.0 g,0.0025 mol) and methanolic ammonia solution (30 ml) was stirred for 15hours at room temperature. The solvent was removed in vacuo and theblack residue was boiled with chloroform and filtered hot. Evaporationof the solvent followed by recrystallisation from ethanol gave thedesired product. Yield 0.33 g (55%), m.p. 163°-165 ° C.

C₁₉ H₁₆ Cl₂ N₄ O

Expected C 58.93, H 4.16, N 14.47, Cl 18.31

Found C 58.96, H 4.35, N 14.39, Cl 18.40

EXAMPLE 52 N-(3-(2,6- Dichlorobenzyloxy)-pyrid-2-yl)-N'-(4-chlorophenyl)guanidine (a)N-(3-(2,6-Dichlorobenzyloxy)-pyrid-2-yl)-N'-(4-chlorophenyl)thiourea

A mixture of 2-amino-3-(2,6-dichlorobenzyloxy)pyridine (5 g, 0.018 mol),4-chlorophenyl isothiocyanate (3.76 g, 0.022 mol) and toluene (20 ml)was heated under reflux for 3 hours, then cooled and diluted with etherto induce crystallisation of the product, which was recrystallised fromethanol/ether. Yield 6.69 g (82%), m.p. 179°-180 ° C.

(b)N-(3-(2,6-Dichlorobenzyloxy)-pyrid-2-yl)-N'-(4-chlorophenyl)guanidine

A mixture of yellow mercuric oxide (1.18g, 0.0054mol),N-[3-(2-,6-dichlorobenzyloxy)pyrid-2-yl]-N'-4-chlorophenylthiourea(2.0g, 0.0045mol) and methanolic ammonia solution (40 ml) was stirredfor 5 days at room temperature. The solvent was removed in vacuo and theblack residue was boiled with chloroform and filtered hot. Evaporationof the solvent followed by recrystallisation from ethanol gave thedesired product. Yield 1.54 g (81%), m.p. 192°-195 ° C.

C₁₉ H₁₅ Cl₃ N₄ O

Expected C 54.11, H 3.59, N 13.29, Cl 25.22

Found C 53.94, H 3.74, N 13.44, Cl25.49

EXAMPLE 53 N-(3-(2,6-Difluorobenzyloxy)-pyrid-2-yl-N'-phenylguanidine(a) N-(3-(2,6-Difluorobenzyloxy)-pyrid-2-yl-N'-phenylthiourea

A mixture of 2-amino-3-(2,6-difluorobenzyloxy)pyridine (2.1 g, 0.09mol), phenyl isothiocyanate (1.43 g, 0.011 mol) and toluene (10 ml) washeated under reflux for 3 hours, then cooled and diluted with ether toinduce crystallisation of the product, which was recrystallised fromethanol/ether. Yield 2.0 g (82%), m.p. 132°-133 ° C.

(b) N-(3-(2,6-Difluorobenzyloxy)-pyrid-2-yl-N'-phenylguanidine

A mixture of yellow mercuric oxide. (0.75g, 0.0034mol),N-[3-(2-,6-difluorobenzyloxy)pyrid-2-yl]-N'-4-chlorophenylthiourea (1.11g, 0.003mol) and methanolic ammonia solution (40 ml) was stirred for 15hours at room temperature. The solvent was removed in vacuo and theblack residue was boiled with chloroform and filtered hot. Evaporationof the solvent followed by recrystallisation from ethanol gave thedesired product. Yield 0.54 g (51%),m.p. 136°-137 ° C.

C₁₉ H₁₆ F₂ N₄ O

Expected C 64.40, H 4.55, N 15.81

Found C 64.16, H 4.73, N 15.81

EXAMPLE 54N-[3-(2,6-Difluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)guanidine (a)N-[3-(2,6-Difluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea

A mixture of 2-amino-3-(2,6-difluorobenzyloxy)pyridine (2.10 g, 0.009mol), 4-chlorophenyl isothiocyanate (1.81 g, 0.01 mol) and toluene (10ml) was refluxed for 3 hours, then cooled and treated with diethyl etherto induce crystallisation of the product. Yield 2.71 g (75%), m.p.151°-154 ° C.

(b) N-[3-(2,6-Difluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)guanidine

A mixture of yellow mercuric oxide (0.75 g, 0.0035 mol),N-[3-(2,6-difluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea(1.18 g, 0.003 mol) and methanolic ammonia solution (40 ml) was stirredfor 2 days at room temperature. The solvent was removed in vacuo and theblack residue was boiled with chloroform and filtered hot. Evaporationof the solvent and recrystallisation from acetonitrile gave the desiredproduct. Yield 0.5 g (44%), m.p. 146°-148 ° C.

C₁₉ H₁₅ ClF₂ N₄ O

Found C 58.74, H 4.03, N 14.49

Expected C 58.70, H 3.89, N 14.41

EXAMPLE 55N-(3-(2,4-Difluorobenzyioxy)pyrid-2-yl)-N'-(4-chlorophenyl)guanidine (a)2-Amino- 3-(2,4-difluorobenzyloxy)pyridine

A mixture of 2-amino-3-hydroxy pyridine (2.66 g, 0.024 mol),dichloromethane (20 ml) and 40% aqueous sodium hydroxide solution (20ml) was stirred for five minutes, then 2,4-difluorobenzyl bromide(5.00g, 0.024 mol) and Adogen 464 (3 ml) were added and stirringcontinued for 16 hours. The mixture was diluted with water and extractedwith dichloromethane. Drying and evaporation of the organic extracts,and trituration with ether gave the desired product. Yield 2.7 g (48%),m.p. 105°-107 ° C.

(b) N-(3-(2,4-Difluorobenzyloxy)pyrid-2-yl)-N'-(4-chlorophenyl)thiourea

A mixture of 2-amino-3-(2,4-difluorobenzyloxy)pyridine (2.10 g, 0.009mol), 4chlorophenyl isothiocyanate (1.81 g, 0.01 mol) and toluene (10ml) was refluxed for 3.5 hours, then cooled and treated with diethylether to induce crystallisation of the product. Yield2.94 g (81%),m.p.154°-156 ° C.

(c) N-(3-(2,4-Difluorobenzyloxy)pyrid-2-yl)-N'-(4-chlorophenyl)guanidine

A mixture of yellow mercuric oxide (0.75 g, 0.034 mol),N-[3-(2,6-difluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea(1.18 g, 0.003 mol)and methanolic ammonia solution (40 ml) was stirredfor 1 day at room temperature. The solvent was removed in vacuo and theblack residue was boiled with chloroform and filtered hot. Evaporationof the solvent, trituration with ether and recrystallisation fromacetonitrile gave the desired product. Yield 0.91 g (78%), m.p. 182°-184° C.

C₁₉ H₁₅ ClF₂ N₄ O

Expected C 58.70, H 3.89, N 14.41, Cl 9.77

Found C 58.78, H 4.13, N 14.44, Cl 10.12

EXAMPLE 56N-[3-(2,4,6-Trifluorobenzyloxy)pyrid-2-yl-N'-(4-chlorophenyl)guanidine(a) 2-Amino- 3-(2,4,6- trifluorobenzyloxy)pyridine

A mixture of 2-amino-3-hydroxy pyridine (2.44 g, 0.022 mol),dichloromethane (20 ml) and 40% aqueous sodium hydroxide solution (20ml) was stirred for five minutes, then 2,4,6-trifluorobenzyl bromide(5.00 g, 0.022 mol) and Adogen 464 (3 ml) were added and stirringcontinued for 16 hours. The mixture was diluted with water and extractedwith dichloromethane. Drying and evaporation of the organic extracts,and trituration with ether gave the desired product. Yield 2.76 g (49%),m.p. 122°-124 ° C.

(b)N-[3-(2,4,6-Trifluorobenzyloxy)pyrid-2-yl-N'-(4-chlorophenyl)thiourea

A mixture of 2-amino-3-(2,4,6-trifluorobenzyloxy)pyridine (2.29 g, 0.009mol), 4chlorophenyl isothiocyanate (1.81 g, 0.01 mol) and toluene (10ml) was refluxed for 3.5 hours, then cooled and treated with diethylether to induce crystallisation of the product. Yield 3.03 g (79.5%),m.p.181°-183 ° C.

(c)N-[3-(2,4,6-Trifluorobenzyloxy)pyrid-2-yl-N'-(4-chlorophenyl)guanidine

A mixture of yellow mercuric oxide (0.74 g, 0.036 mol),N-[3-(2,4,6-trifluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea(1.27 g, 0.003 mol) and methanolic ammonia solution (40 ml) was stirredfor 1 day at room temperature. The solvent was removed-in vacuo and theblack residue was boiled with chloroform and filtered hot. Evaporationof the solvent, trituration with ether and recrystallisation fromacetonitrile gave the desired product. Yield 0.63 g (52%), m.p. 161°-162° C.

C₁₉ H₁₄ ClF₃ N₄ O

Expected C 56.10, H 3.47, N 13.77, Cl 8.72

Found C 56.18, H 3.69, N 13.88, Cl 8.85

EXAMPLE 57N-(3-(2,3,6-Trifluorobenzyloxy)pyrid-2-yl)-N'-(4-chlorophenyl)guanidine(a) 2-Amino-3-(2,3,6-trifluorobenzyloxy)pyridine

A mixture of 2-amino-3-hydroxy pyridine (2.44 g, 0.022 mol),dichloromethane (20 ml) and 40% aqueous sodium hydroxide solution (20ml) was stirred for five minutes, then 2,3,6-trifluorobenzyl bromide(5.00 g, 0.022 mol) and Adogen 464 (3 ml) were added and stirringcontinued for 16 hours. The mixture was diluted with water and extractedwith dichloromethane. Drying and evaporation of the organic extracts,and trituration with ether gave the desired product. Yield 2.94 g (53%),m.p. 108°-110 ° C.

(b)N-(3-(2,3,6-Trifluorobenzyloxy)pyrid-2-yl)-N'-(4-chlorophenyl)thiourea

A mixture of 2-amino-3-(2,3,6-trifluorobenzyloxy)pyridine (2.00 g,0.0078 mol), 4chlorophenyl isothiocyanate (1.6 g, 0.094 mol) and toluene(10 ml) was refluxed for 3 hours, then cooled and treated with diethylether to induce crystallisation of the product. Yield 2.82 g (85.5%),m.p.174°-176 ° C.

(c)N-(3-(2,3,6-Trifluorobenzyloxy)pyrid-2-yl)-N'-(4-chlorophenyl)guanidine

A mixture of yellow mercuric oxide (1.23g, 0,056 mol),N-[3-(2,3,6-trifluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea(2.00g 0.0047mol) and methanolic ammonia solution (40 ml) was stirredfor 1 day at room temperature. The solvent was removed in vacuo and theblack residue was boiled with chloroform and filtered hot. Evaporationof the solvent, trituration with ether and recrystallisation fromacetonitrile gave the desired product. Yield 1.20 g (63%), m.p. 153°-156° C.

C₁₉ H₁₄ ClF₃ N₄ O

Expected C 56.10, H 3.47, N 13.77, Cl 8.72

Found C 56.09, H 3.68, N 13.80, Cl 8.81

EXAMPLE 58N-(3-(2-Fluoro-4-methoxybenzyloxy)pyrid-2-yl)-N'-(4-chlorophenyl)guanidine(a) 2-Amino-3-(2-fluoro-4-methoxybenzyloxy)pyridine

A mixture of 2-amino-3-hydroxy pyridine (1.45g, 0.013 mol),dichloromethane (10 ml) and 40% aqueous sodium hydroxide solution (10ml) was stirred for five minutes, then 2-fluoro-4-methoxybenzyl bromide(2.9 g, 0.013 mol) and Adogen 464 (1.5 ml) were added and stirringcontinued for 16 hours. The mixture was diluted with water and extractedwith dichloromethane. Drying and evaporation of the organic extracts,and trituration with ether gave the desired product. Yield 1.11 g (34%),m.p. 135°-138 ° C.

(b)N-(3-(2-Fluoro-4-methoxybenzyloxy)pyrid-2-yl)-N'-(4-chlorophenyl)thiourea

A mixture of 2-amino-3-(2-fluoro-4-methoxylbenzyloxy)pyridine (1.00 g,0.004 mol), 4chlorophenyl isothiocyanate (0.68 g, 0.0048 mol) andtoluene (10 ml) was refluxed for 3 hours, then cooled and treated withdiethyl ether to induce crystallisation of the product.Yield0.86g(51%),m.p.138°-140° C.

(c)N-(3-(2-Fluoro-4-methoxybenzyloxy)pyrid-2-yl)-N'-(4-chlorophenyl)guanidine

A mixture of yellow mercuric oxide (0.54 g, 0.0025 mol),N-[3-(2-fluoro-4-methoxybenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea(0.8 g, 0.0021 mol) and methanolic ammonia solution (40 ml) was stirredfor 2 days at room temperature. The solvent was removed in vacuo and theblack residue was boiled with chloroform and filtered hot. Evaporationof the solvent followed by trituration with ether and recrystallisationfrom acetonitrile gave the desired product. Yield 0.37 g, (45%), m.p.158°-161 ° C.

C₂₀ H₁₈ ClFN₄ O

Expected C 59.93, H 4.53, N 13.98, Cl 8.84

Found C 59.63, H 4.66, N 14.13, Cl 8.46

EXAMPLE 59N-[3-(3-Chloro-2-fluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)guanidine(a) 2-Amino- 3-(3-chloro-2-fluorobenzyloxy)pyridine

A mixture of 2-amino-3-hydroxypyridine (2.42 g, 0.022 mol),dichloromethane (20 ml) and 40% aqueous sodium hydroxide solution (20ml) was stirred for five minutes, then 3-chloro-2-fluorobenzyl bromide(5.0 g, 0.022 mol) and Adogen 464 (3 ml) were added and stirringcontinued for 16 hours. The mixture was diluted with water and extractedwith dichloromethane. Drying and evaporation of the organic extracts,and trituration with ether gave the desired product. Yield 3.22 g (58%),m.p. 98°-100 ° C.

(b)N-[3-(3-Chloro-2-fluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea

A mixture of 2-amino-3-(3-chloro-2-fluorobenzyloxy)pyridine (2.00 g,0.0079 mol), 4chlorophenyl isothiocyanate (1.61 g, 0.0095 mol) andtoluene (10 ml) was refluxed for 3 hours, then cooled and treated withdiethyl ether to induce crystallisation of the product. Yield2.37 g(71%),m.p. 174°-176 ° C.

(c)N-[3-(3-Chloro-2-fluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)guanidine

A mixture of yellow mercuric oxide (1.23 g, 0.0047 mol),N-[3-(3-chloro-2-fluorobenzyloxy)pyrid-2-yl]-N'-4-chlorophenylthiourea(2.0 g, 0.0047 mol) and methanolic ammonia solution (40 ml) was stirredfor 2 days at room temperature. The solvent was removed in vacuo and theblack residue was boiled with chloroform and filtered hot. Evaporationof the solvent followed by trituration with ether and recrystallisationfrom acetonitrile gave the desired product. Yield 0.38 g (20%), m.p.204°-207 ° C.

C₁₉ H₁₅ Cl₂ FN₄ O.0.07CHCl₃

Expected C 55.37, H 3.67, N 13.55, Cl 18.94

Found C 55.36, H 3.81, N 13.55, Cl 18.97

EXAMPLE 60N-[3-(2-Fluoro-3-methylbenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)guanidine(a) 2-Amino-3-(2-fluoro-3-methylbenzyloxy)pyridine

A mixture of 2-amino-3-hydroxypyridine (2.8 g, 0.026 mol),dichloromethane (20 ml) and 40% aqueous sodium hydroxide solution (20ml) was stirred for five minutes, then 2-fluoro-3-methylbenzyl bromide(5.0 g, 0.026 mol) and Adogen 464 (3 ml) were added and stirringcontinued for 16 hours. The mixture was diluted with water and extractedwith dichloromethane. Drying and evaporation of the organic extracts,and trituration with ether gave the desired product. Yield 3.99 g (66%),m.p. 115°-118 ° C.

(b)N-[3-(2-Fluoro-3-methylbenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea

A mixture of 2-amino-3-(2-fluoro-3-methylbenzyloxy)pyridine (2.00 g,0.0086 mol), 4chlorophenyl isothiocyanate (1.75 g, 0.0103 mol) andtoluene (10 ml) was refluxed for 3 hours, then cooled and treated withdiethyl ether to induce crystallisation of the product. Yield 3.21g(93%), m.p. 184°-187 ° C.

(c)N-[3-(2-Fluoro-3-methylbenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)guanidine

A mixture of yellow mercuric oxide (1.29 g, 0.0059 mol),N-[3-(2-fluoro-3-methylbenzyloxy)pyrid-2-yl]-N'-4-chlorophenylthiourea(2.0g, 0.0049 mol) and methanolic ammonia solution (40 ml) was stirredfor 2 days at room temperature. The solvent was removed in vacuo and theblack residue was boiled with chloroform and filtered hot. Evaporationof the solvent followed by trituration with ether and recrystallisationfrom acetonitrile gave the desired product. Yield 1.59g, (84.5%), m.p.179°-181 ° C.

C₂₀ H₁₈ ClFN₄ O.0.04CHCl₃

Expected C 61.77, H 4.66, N 14.38, Cl 10.19

Found C 62.04, H 4.79, N 14.53, Cl 10.24

EXAMPLE 61N-(3-(2,4,6-Trimethylbenzyloxy)pyrid-2-yl)-N'-(4-chlorophenyl)guanidine(a) 2-Amino- 3-(2,4,6-trimethylbenzyloxy)pyridine

A mixture of 2-amino-3-hydroxy pyridine (29.6 g, 0.269 mol),dichloromethane (200 ml) and 40% aqueous sodium hydroxide solution (200ml) was stirred for five minutes, then 2,4,6-trimethylbenzyl bromide (50g, 0.296 mol) and Adogen 464 (5 ml) were added and stirring continuedfor 16 hours. The mixture was diluted with water and extracted withdichloromethane. Drying and evaporation of the organic extracts, andtrituration with ether gave the desired product. Yield 29.6 g (41%),m.p. 160°-166 ° C.

(b)N-(3-(2,4,6-Trimethylbenzyloxy)pyrid-2-yl)-N'-(4-chlorophenyl)thiourea

A mixture of 2-amino-3-(2,4,6-trimethylbenzyloxy)pyridine (2.00 g,0.0082 mol), 4chlorophenyl isothiocyanate (1.68 g, 0.0099 mol) andtoluene (10 ml) was refluxed for 3 hours, then cooled and treated withdiethyl ether to induce crystallisation of the product. Yield 2.37 g(70%), m.p. 180°-182 ° C.

(c)N-(3-(2,4,6-Trimethylbenzyloxy)pyrid-2-yl)-N'-(4-chlorophenyl)guanidine

A mixture of yellow mercuric oxide (0.95 g, 0.0044 mol),N-[3-(2,4,6-trimethylbenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea(1.5 g, 0.0036 mol) and methanolic ammonia solution (40 ml) was stirredfor 2 days at room temperature. The solvent was removed in vacuo and theblack residue was boiled with chloroform and filtered hot. Evaporationof the solvent followed by trituration with ether and recrystallisationfrom acetonitrile gave the desired product. Yield 1.16 g (82%), m.p.169°-171 ° C.

C₂₂ H₂₃ ClN₄ O

Expected C 66.91, H 5.87, N 14.19, Cl 8.98

Found C 66.94, H 5.90, N 14.47, Cl 9.17

EXAMPLE 62N-[3-(2-Chloro6-fluorobenzyloxy)-5-chloropyrid2-yl]-N'-(4-chlorophenyl)guanidine(a) 2-Amino-N-[3-(2-chloro-6-fluorobenzyloxy)-5-chloropyridine

A mixture of 2-amino-3-hydroxy-5-chloropyridine (1.4 g, 0.313 mol),dichloromethane (5 ml) and 40% aqueous sodium hydroxide solution (5 ml)was stirred for five minutes, then 2-chloro-6-fluorobenzyl chloride(1.96 g, 0.019 mol) and Adogen 464 (0.5 ml) were added and stirringcontinued for 16 hours. The mixture was diluted with water and extractedwith dichloromethane. Drying and evaporation of the organic extracts andtrituration with ethanol gave the desired product. Yield 0.93 g (32%),m.p. 132°-133 ° C.

(b)N-[3-(2-Chloro-6-fluorobenzyloxy)-5-chloropyrid-2-yl]-N'-(4chlorophenyl)thiourea

A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)-5-chloropyridine(0.82 g, 0.0028 mol), 4-chlorophenyl isothiocyanate (0.56 g, 0.0033 mol)and toluene (10 ml) was heated under reflux for 16 hours, then cooledand diluted with ether to induce crystallisation of the product, whichwas triturated with ethanol. Yield 0.68 g (54%), m.p. 158°-160 ° C.

(c)N-[3-(2-Chloro-6-fluorobenzyloxy)-5-chloropyrid-2-yl]-N'-(4chlorophenyl)guanidine

A mixture of yellow men:uric oxide (0.36 g, 0.0017 mol),N-[3-(2-chloro-6-fluorobenzyloxy)-5-chloropyrid-2-yl]-N'-4-chlorophenylthiourea(0.64 g, 0.0014 mol)and methanolic ammonia solution (20 ml) was stirredfor 1 day at room temperature. The solvent was removed in vacuo and theblack residue was boiled with chloroform and filtered hot. Evaporationof the solvent followed by recrystallisation from ethanol gave thedesired product. Yield 0.09 g (15%), m.p. 162°-163 ° C.

C₁₉ H₁₄ Cl₃ FN₄ O

Expected C 51.67, H 3.20, N 12.74, Cl 24.19

Found C 51.72, H 3.20, N 12.78, Cl23.11

EXAMPLE 63 N-[3-(2-Chloro-6-fluorobenzyloxy)-6-methylpyrid-2-yl]-N'-(4

chlorophenyl)guanidine

(a) 2-Amino- 3-(2-chloro-6-fluorobenzyloxy)-6-methylpyridine

A mixture of 2-amino-3-hydroxy-6-methylpyridine (4.3 g, 0.035 mol),dichloromethane (26 ml) and 40% aqueous sodium hydroxide solution (26ml) was stirred for five minutes at room temperature, then2-chloro-6-fluorobenzyl chloride (6.8 g, 0.038 mol) and Adogen 464 (2.5ml) were added and stirring continued for 16 hours. The mixture wasdiluted with water and extracted with dichloromethane. Drying andevaporation of the organic extracts and trituration with ethanol gavethe desired product. Yield 6.3 g (67%), m.p. 108°-109 ° C.

(b)N-[3-(2-Chloro-6-fluorobenzyloxy)-6-methylpyrid-2-yl]-N'-(4chlorophenyl)thiourea

A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)-6-methylpyridine(2.0 g, 0.0075 mol), 4-chlorophenyl isothiocyanate (1.53 g, 0.0089 mol)and toluene (10 ml) was heated under reflux for 2 hours, then cooled anddiluted with ether to induce crystallisation of the product, which wastriturated with ethanol. Yield 2.6 g (82%), m.p. 204°-205 ° C.

(c)N-[3-(2-Chloro-6-fluorobenzyloxy)-6-methylpyrid-2-yl]-N'-(4chlorophenyl)guanidine

A mixture of yellow mercuric oxide (0.58 g, 0.0027 mol),N-[3-(2-chloro-6-fluorobenzyloxy)-6-methylpyrid-2-yl]-N'-4-chlorophenylthiourea(1.00 g, 0.0023 mol) and methanolic ammonia solution (30 ml) was stirredfor 2 days at room temperature. The solvent was removed in vacuo and theblack residue was boiled with chloroform and filtered hot. Evaporationof the solvent followed by recrystallisation from ethanol gave thedesired product. Yield 0.52 g (54%), m.p. 148°-149 ° C.

C₂₀ H₁₇ Cl₂ FN₄ O

Expected C 57.29, H 4.09, N 13.36, Cl 16.91

Found C 57.34, H 4.20, N 13.39, Cl 17.62

EXAMPLE 64 N-(3-(2,6-Dichlorobenzyloxy)pyrid-2-yl)-N'-methyl-N"-(4-chlorophenyl)guanidine

A mixture ofN-[3-(2,6-dichlorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (2.0g, 0.0045 mol), yellow mercuric oxide (1.18 g, 0.0054 mol) and 33% w/wmethylamine in methylated spirit (40 ml) was stirred at room temperaturefor 24 hours. The solvent was removed in vacuo and the black residue wasboiled with chloroform and filtered hot. Evaporation of the solvent andrecrystallisation from acetonitrile gave the desired product. Yield 1.53g (78%), m.p. 153°-156 ° C.

C₂₀ H₁₇ Cl₃ N₄ O

Expected C 55.13, H 3.93, N 12.86, Cl 24.41

Found C 55.01, H 4.07, N 12.95, Cl 24.50

EXAMPLE 65N-[3-(2,6-Difluorobenzyloxy)pyrid-2-yl]-N'-methyl-N'-(4-chlorophenyl)guanidine

A mixture ofN-[3-(2,6-difluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea(0.93 g, 0.002 mol), yellow mercuric oxide (0.52 g, 0.0024 mol) and 33%w/w methylamine in methylated spirit (45 ml) was stirred at roomtemperature for 3 days. The solvent was removed in vacuo and the blackresidue was boiled with chloroform and filtered hot. Evaporation of thesolvent, trituration with ether and recrystallisation from acetonitrilegave the desired product. Yield 0.44 g (48%), m.p. 100°-102 ° C.

C₂₀ H₁₇ ClF₂ N₄ O

Found C 59.81, H 4.43, N 14.05

Expected C 59.63, H 4.25, N 13.91

EXAMPLE 66N-(3-(2,6-Difluorobenzyloxy)pyrid-2-yl-N'-(prop-1-yl)-N"-(4-chlorophenyl)guanidine

A mixture ofN-[3-(2,6-difluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (1.0g, 0.0025 mol), yellow mercuric oxide (0.64 g, 0.003 mol) andn-propylamine (20 ml) was stirred at room temperature for 48 hours. Thesolvent was removed in vacuo and the black residue was boiled withchloroform and filtered hot. Evaporation of the solvent andrecrystallisation from acetonitrile gave the desired product. Yield 0.60g (48%), m.p. 99°-100 ° C.

C₂₂ H₂₁ ClF₂ N₄ O

Expected C 61.33, H 4.91, N 13.00, Cl 8.23

Found C 60.78, H 4.95, N 12.96, Cl 8.49

EXAMPLE 67N-(3-(2,6-Difluorobenzyloxy)pyrid-2-yl-N'-(prop-2-yl)-N-"-(4-chlorophenyl)guanidine

A mixture ofN-[3-(2,6-difluorobenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (1.0g, 0.0025 mol), yellow mercuric oxide (0.64 g, 0.003 mol) andisopropylamine (0.43 g, 0.0074 mol) in methanol (20 ml) was stirred atroom temperature for 96 hours, and then heated at 50 ° C. for 8 hours.After cooling, the solvent was removed in vacuo and the black residuewas boiled with chloroform and filtered hot. Evaporation of the solventand recrystallisation from acetonitrile gave the desired product. Yield0.24 g (23%), m.p. 112°-113 ° C.

C₂₂ H₂₁ ClF₂ N₄ O

Expected C 61.33, H 4.91, N 13.00, Cl 8.23

Found C 60.34, H 4.93, N 13.10, Cl 8.44

EXAMPLE 68 N-[3-(2-Chloro-6-fluorobenzyloxy)pyrid-2-yl]-N'-methyl-N'-phenylguanidine (a)N-[3-(2-chloro-6-fluorobenzyloxy)pyrid-2-yl)-N -benzoylthiourea

A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)-6-methylpyridine(5.0 g, 0.0197 mol), 4-benzoylisothiocyanate (3.8 g, 0.024 mol) andether (100 ml) was stirred at room temperature for 2 hours, then thesolid formed was filtered and washed with pet. ether to give the desiredproduct. Yield 7.31 g (90%), m.p. 136°-138 ° C.

(b)N-[3-(2-chloro-6-fluorobenzyloxy)pyrid-2-yl-N-benzoyl-N-(methylanilino)guanidine

A mixture of N-[3-(2,6-difluorobenzyloxy)pyrid-2-yl]-N'-benzoylthiourea(5.0 g, 0.012 mol), yellow mercuric oxide (3.1 g, 0.014 mol) andN-methylaniline (3.9 ml, 0.036 mol) in methanol (200 ml) was stirred atroom temperature for 16 hours, followed by 2 hours at 70 ° C. Themixture was cooled, the solvent was removed in vacuo and the blackresidue was boiled with chloroform and filtered hot. Evaporation of thesolvent followed by chromatography (silica gel, chloroform) gave thedesired product as an oil. Yield 4.73 g (80%).

(c) N-[3-(2-chloro-6-fluorobenzyloxy)pyrid-2-yl]-N-methyl-N-phenylguanidine

A mixture ofN-[3-(2-chloro-6-fluorobenzyloxy)pyrid-2-yl-N-benzoyl-N-(methylanilino)guanidine(0.47 g, 0.00098 mol), hydrochloric acid (2N, 10 ml) and ethanol (3 ml)was refluxed for 16 hours, cooled, filtered and recrystallised fromethanol/ether to give the required product. Yield 0.08 g (20%) m.p.223°-225 ° C.

C₂₀ H₁₈ ClFN4O.0.9HCl.0.5H₂ O

Expected C 56.24, H 4.70, N 13.11, Cl 15.78

Found C 56.44, H 4.67, N 12.97, Cl15.82

Biological Data. H⁺ K⁺ ATPase Activity.

The effects of a single high concentration (100 μM) of a compound ofstructure (I) on K-stimulated ATPase activity in lyophilised gastricvesicles was determined. Preferred compounds of structure (I) were alsotested over a range of concentrations to determine IC₅₀ values.

(i) Preparation of lyophilised gastric vesicles (H/K-ATPase).

Lyophilised gastric vesicles were prepared from pig fundic mucosa afterthe method of Keeling et. al. (Biochem. Pharmacol., 34, 2967, 1985).

(ii) K⁺ -stimulated ATPase activity.

K⁺ -stimulated ATPase activity was determined at 37° C. in the presenceof the following: 10 mM Pipes/Tris buffer pH 7.0, 2 mM MgSO₄, 1 mM KCl,2 mM Na₂ ATP and 3-6 μg protein/ml lyophilised gastric vesicles. Afterincubation for 30 minutes, the inorganic phosphate hydrolysed from ATPwas determined by the method of Yoda and Hokin (Biochem. Biophys. Res.Commun. 40, 880, 1970).

Compounds of structure (I) were dissolved in dimethylsulphoxide which upto the highest concentration used had no effect on K⁺ -stimulated ATPaseactivity.

The effect of the highest concentration of each compound of structure(I) on the recovery of a standard mount of inorganic phosphate was alsodetermined.

Results

The compounds of the examples exhibited IC50 values of less than 5.5 μM.

We claim:
 1. A compound of structure (I): ##STR6## in which: Ar¹ is anoptionally substituted phenyl ring;Ar² is an optionally substitutedphenyl ring; R¹ is hydrogen or C₁₋₄ alkyl; R² is hydrogen or C₁₋₄ alkyl;R³ is hydrogen or C₁₋₄ alkyl; R⁴ is hydrogen, halogen, C₁₋₆ alkyl orC₁₋₆ alkoxy, X is CH₂ or NR⁵, and R⁵ is hydrogen or C₁₋₄ alkyl, or asalt thereof.
 2. A compound according to claim 1 in which R¹ to R⁴ areall hydrogen.
 3. A compound according to claim 2 in which Ar¹ is aphenyl ring substituted by two halogen atoms.
 4. A compound according toclaim 3 in which Ar² is a phenyl ring substituted by a single halogenatom.
 5. A pharmaceutical composition comprising a compound according toclaim 1 or a pharmaceutically acceptable salt thereof, in associationwith a pharmaceutically acceptable carrier.
 6. A compound according toclaim 1 for use in the treatment of gastrointestinal disorders.